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NZ741411B2 - Cyanopyrrolidines with activity as inhibitors of deubiquitylating enzymes (DUBs) - Google Patents
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NZ741411B2 - Cyanopyrrolidines with activity as inhibitors of deubiquitylating enzymes (DUBs) - Google Patents

Cyanopyrrolidines with activity as inhibitors of deubiquitylating enzymes (DUBs)

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Publication number
NZ741411B2
NZ741411B2 NZ741411A NZ74141116A NZ741411B2 NZ 741411 B2 NZ741411 B2 NZ 741411B2 NZ 741411 A NZ741411 A NZ 741411A NZ 74141116 A NZ74141116 A NZ 74141116A NZ 741411 B2 NZ741411 B2 NZ 741411B2
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New Zealand
Prior art keywords
methyl
cyanopyrrolidinyl
alkyl
amino
mmol
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Application number
NZ741411A
Other versions
NZ741411A (en
Inventor
Mark Ian Kemp
Andrew Madin
Martin Lee Stockley
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Mission Therapeutics Limited
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Priority claimed from GBGB1522267.2A external-priority patent/GB201522267D0/en
Application filed by Mission Therapeutics Limited filed Critical Mission Therapeutics Limited
Publication of NZ741411A publication Critical patent/NZ741411A/en
Publication of NZ741411B2 publication Critical patent/NZ741411B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/04—Ortho-condensed systems

Abstract

The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C- terminal hydrolase 30 or Ubiquitin Specific Peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c, R1d, R1e, R1f, R1g, R2, X, L and A are as defined herein. the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c, R1d, R1e, R1f, R1g, R2, X, L and A are as defined herein.

Description

Cyanopyrrolidines with activity as inhibitors of deubiquitylating enzymes (DUBs) The t invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes . In particular, the invention relates to the inhibition of ubiquitin C- terminal hydrolase 30 or ubiquitin specific peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and in the treatment of cancer.
Background to the Invention The listing or discussion of an apparently prior-published nt in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Ubiquitin is a small protein ting of 76 amino acids that is important for the regulation of protein function in the cell. Ubiquitylation and deubiquitylation are enzymatically ed processes by which ubiquitin is covalently bound or cleaved from a target protein by deubiquitylating enzymes (DUBs), of which there are approximately 95 DUBs in human cells, divided into sub-families based on sequence homology. The USP family are characterised by their common Cys and His boxes which contain Cys and His residues critical for their DUB activities. The ubiquitylation and deubiquitylation ses have been implicated in the regulation of many cellular ons including cell cycle progression, apoptosis, modification of cell e receptors, regulation of DNA transcription and DNA repair. Thus, the ubiquitin system has been implicated in the pathogenesis of numerous disease states including inflammation, viral infection, metabolic dysfunction, CNS disorders, and nesis (Clague et al., l Rev 93:1289-1315, 2013).
Ubiquitin is a master regulator of mitochondrial dynamics. Mitochondria are dynamic lles whose biogenesis, fusion and fission events are regulated by the post-translational regulation via ubiquitylation of many key factors such as mitofusins. While tin ligases such as parkin are known to ubiquitylate a number of mitochondrial proteins, until recently, deubiquitylating enzymes remained elusive. USP30 is a 517 amino acid protein which is found in the mitochondrial outer membrane (Nakamura et al., Mol Biol 19:1903-11, 2008). It is the sole deubiquitylating enzyme bearing a ondrial addressing signal and has been shown to deubiquitylate a number of ondrial proteins. It has been demonstrated that USP30 opposes parkin-mediated mitophagy and that reduction of USP30 activity can rescue parkin-mediated defects in agy (Bingol et al., Nature 510:370-5, 2014).
Mitochondrial dysfiJnction can be defined as diminished mitochondrial content (mitophagy or ondrial biogenesis), as a decrease in mitochondrial activity and oxidative phosphorylation, but also as tion of reactive oxygen species (ROS) generation. Hence a role for mitochondrial dysfiJnctions in a very large number of aging processes and ogies including but not limited to, egenerative diseases (e.g. son’s disease (PD), Alzheimer’s disease, Huntington’s disease, Amylotrophic Lateral Sclerosis (ALS), multiple sclerosis), cancer, diabetes, metabolic disorders, cardio-vascular diseases, psychiatric diseases (e.g. Schizophrenia), and osteoarthritis.
For example, son’s disease affects around 10 million people worldwide (Parkinson’s Disease Foundation) and is characterised by the loss of dopaminergic neurons in the substantia nigra. The exact mechanisms underlying PD are unclear, however mitochondrial dysfiJnction is increasingly appreciated as a key determinant of dopaminergic neuronal tibility in PD and is a feature of both familial and ic disease, as well as in toxin-induced Parkinsonism. Parkin is one of a number of proteins that have been implicated with early onset PD. While most PD cases are linked to defects in synuclein, 10% of Parkinson’s cases are linked to specific genetic defects, one of which is in the ubiquitin E3 ligase parkin. Parkin and the n kinase PTEN-induced putative kinase 1 (PINKl) collaborate to ubiquitylate mitochondrial membrane proteins of damaged mitochondria resulting in mitophagy. Dysregulation of mitophagy results in increased oxidative stress, which has been described as a characteristic of PD. Inhibition of USP30 could therefore be a potential strategy for the treatment of PD. For example, PD patients with parkin mutations leading to reduced activity could be therapeutically compensated by inhibition of USP30.
It has been reported that depletion of USP30 enhances mitophagic clearance of ondria and also enhances parkin-induced cell death (Liang et al., EMBO Reports 2015 DOI: .15252/embr.201439820). USP30 has also been shown to regulate BAX/BAK-dependent apoptosis independently of parkin over expression. Depletion of USP30 sensitises cancer cells to BH-3 mimetics such as 7, without the need for parkin over expression. Thus, an anti-apoptotic role has been demonstrated for USP30 and USP30 is therefore a potential target for anti-cancer therapy.
The tin-proteasome system has gained interest as a target for the ent of cancer following the approval of the proteasome inhibitor bortezomib (Velcade®) for the treatment of multiple myeloma. Extended treatment with bortezomib is d by its ated toxicity and drug resistance. However, therapeutic strategies that target specific aspects of the ubiquitin-proteasome pathway upstream of the proteaseome, such as DUBs, are predicted to be better ted (Bedford et al., Nature Rev 10:29-46, 2011). Thus, there is a need for compounds and pharmaceutical compositions to inhibit DUBs such as USP30 for the treatment of indications where DUB activity is observed, including, although not limited to, conditions involving ondrial dysfunction and cancer. y of the ion The present invention broadly relates to compounds of formula (I) or a ceutically acceptable salt thereof, wherein: R1b, R1c, R1d, R1e each independently represent hydrogen or an optionally substituted C1-C6 alkyl, or R1b is linked to R1a or R1c to form an optionally substituted cycloalkyl ring, or R1e is linked to R1d or R1f to form an ally substituted cycloalkyl ring; R1a and R1g each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, or R1a and R1g together form an optionally tuted cycloalkyl ring, or R1a is linked to R1b to form an optionally substituted cycloalkyl ring, or R1g is linked to R1f to form an optionally substituted cycloalkyl ring; R1f represents hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R1f is linked to R1g or R1e to form an optionally substituted cycloalkyl ring, or R1f together with R2 forms an optionally r substituted heterocyclic ring; R2 represents hydrogen, optionally substituted C1-C6 alkyl or R2 together with R1f forms an optionally further substituted heterocyclic ring; X is C(R3)(R4), wherein R3 and R4 each independently represent hydrogen, cyano, optionally substituted C1-C6 alkyl, a 5 or 6 membered heteroaryl or aryl ring or R3 and R4 together form an optionally substituted 3 to 6 membered heteroalkyl or cycloalkyl ring; L represents a nt bond, -SO-, -SO2-, , -C(O)O-, -CONR5-, -SO2NR5-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C2-C6 lene-C(O)-, -C1-C6 alkylene- , -C1-C6 alkylene-CONR5-, optionally substituted C1-C6 alkylene or optionally substituted - C2-C6 alkenylene; A ents a substituted monocyclic heteroaryl or aryl ring or an optionally substituted bicyclic heteroaryl or aryl ring; R5 represents hydrogen or optionally tuted C1-C6 alkyl.
Accordingly in a first aspect, the present invention provides a compound of formula (I): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R1b, R1c, R1d, R1e each ndently represent hydrogen or C1-C6 alkyl; R1a and R1g each ndently represent hydrogen, fluorine, cyano, yl, amino, C1-C6 alkyl or C1-C6 alkoxy; R1f represents hydrogen, fluorine, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy, or R1f together with R2 forms a 5-membered cyclic ring; R2 represents hydrogen or C1-C6 alkyl, or R2 together with R1f forms a 5-membered heterocyclic ring; X is C(R3)(R4), wherein R3 and R4 each independently represent hydrogen, cyano or C1-C6 alkyl; L represents a covalent bond, -SO-, -SO2-, -C(O)-, -C(O)O-, -CONR5-, -SO2NR5-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C1-C6 ne or -C2-C6 alkenylene; A represents a substituted 5 to 10-membered monocyclic, heteroaryl or aryl ring, or an optionally substituted 9 to 10-membered bicyclic, heteroaryl or aryl ring; R5 represents hydrogen or C1-C6 alkyl; wherein ring A, when substituted, is substituted with one to four -Q1-(R6)n, n each occurrence of -Q1-(R6)n is the same or different; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR7, -SR7, -NR7R8, -CONR7R8, -NR7COR8, - NR7CONR8R9, -COR7, -C(O)OR7, -NR7C(O)OR8, -C1-C6 alkyl, -C1-C6 alkoxy, a covalent bond, an oxygen atom, a sulphur atom, C1-C6 alkylene or -C2-C6 alkenylene; R6 is a 3 to 10-membered heterocyclyl, saturated lkyl, heteroaryl or aryl ring; R7, R8 and R9 each independently represent hydrogen, C1-C6 alkyl or C1-C6 alkylene; wherein R6 is optionally substituted with one to four substituents, each ndently selected from halogen, cyano, oxo, nitro, -OR10, -SR10, -NR10R11, -C1-C6 alkyl and -C1-C6 alkoxy; R10 and R11 each independently represent hydrogen or C1-C6 alkyl; wherein the heterocyclic ring formed by R1f together with R2 is optionally further substituted with oxo; and wherein said C1-C6 alkyl and C1-C6 alkoxy are each independently optionally tuted with one to four substituents, each independently selected from halogen, hydroxyl, thiol, cyano, amino, nitro and In some aspects, the invention also relates to pharmaceutical itions comprising the nds of the present invention and one or more pharmaceutically acceptable excipients.
Accordingly in a second , the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the first aspect, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.
In other s, the compounds of the invention are useful for the treatment of cancer or a e or condition involving mitochondrial dysfunction.
Accordingly in a third , the present invention provides use of a compound according to the first aspect, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the ent of a condition involving mitochondrial dysfunction.
In a fourth aspect, the present invention provides use of a nd according to the first aspect, a tautomer thereof, or a pharmaceutically able salt of said compound or tautomer, in the manufacture of a medicament for the treatment of cancer linked to USP30 activity.
Brief Description of the Figures Figure 1 is a graph showing proteolytic activity of USP30 measured using a fluorescence polarisation assay. Various volumes of purified USP30 as ted were incubated with a TAMRA labelled peptide linked to ubiquitin via an isopeptide bond.
Detailed Description of the Invention The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims. nce to compounds as described herein (e.g. a compound of formula (I)), includes nce to formula (I) including any sub-generic embodiments thereof, e.g. formula (IA).
Where any group of the compounds of formula (I) has been referred to as optionally substituted, this group may be substituted or unsubstituted. Substitution may be by one or more of the specified substituents which may be the same or different. It will be appreciated that the number and nature of substituents will be selected to avoid any sterically undesirable combinations.
In the t of the present specification, unless otherwise stated an alkyl, alkylene, alkoxy, alkenyl, or alkynyl substituent (or ) group or an alkyl, alkenyl moiety in a substituent group may be linear or branched. Alkyl, alkylene and alkenyl chains may also include intervening heteroatoms such as oxygen.
Cx-Cy alkyl refers to a ted aliphatic hydrocarbon group having x-y carbon atoms which may be linear or branched. For example C1-C6 alkyl contains from 1 to 6 carbon atoms and includes C1, C2, C3, C4, C5 and C6. "Branched" means that at least one carbon branch point is present in the group.
For example, tert-butyl and isopropyl are both branched groups. Examples of C1-C6 alkyl groups e , ethyl, propyl, 2-methylpropyl, 2-methylpropyl, 2-methylbutyl, 3-methyl butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2-methyl-pentyl, 3-methylpentyl, 4-methyl pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethyl- 1-butyl, 2-ethylbutyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and l. C1- 4b (followed by page 5) C6 alkyl, C1-C4 alkyl and C1-C3 alkyl within the definitions of R13, R", R": R1", R16, R", 111%, R2, R3, R4, R5, R7, R8, R9, R10, R", R", Q, and within the definition of tuents for R6, may be tituted or substituted with one or more of the substituents defined herein. Examples of substituted C1-C6 alkyl therefore include CF3, CH2CF3, CHZCN, CHZOH and CHZCHZOH.
A Cx-Cy alkylene group or moiety may be linear or branched and refers to a divalent hydrocarbon group having one less hydrogen atom from CX_Cy alkyl as defined above. C1-C6 alkylene may include intervening heteroatoms such as oxygen, and therefore includes alkyleneoxy groups. Alkyleneoxy as employed herein also extends to embodiments in which the or an oxygen atom (e.g. a single oxygen atom) is located within the alkylene chain, for example CHZCHZOCHZ or CHZOCHZ. Examples of C1.
C6 ne groups include methylene, methyleneoxy, ethylene, ethyleneoxy, ylene, n- propyleneoxy, n-butylene, n-butyleneoxy, methylmethylene and dimethylmethylene. Unless stated otherwise, C1-C6 alkylene, C1-C4 ne and C1-C3 alkylene within the definitions of R7, R8, R9, L, Q1 and Q2 may be unsubstituted or tuted with one or more of the substituents defined herein.
C2-C6 alkenyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon atoms and at least one double bond and includes C2-C4 l. Examples of alkenyl groups include ethenyl, propenyl, 2-propenyl, l-butenyl, 2-butenyl, l-hexenyl, 2-methyl-l-propenyl, l,2—butadienyl, 1,3-pentadienyl, l,4-pentadienyl and l-hexadienyl. Unless stated otherwise, C2-C6 alkenyl within the definitions of Q1 and within the definition of substituents for R6, may be unsubstituted or substituted with one or more of the substituents defined herein.
C2-C6 alkenylene refers to linear or branched hydrocarbon group having one less hydrogen atom from C2-C6 alkenyl as defined above. Examples of C2-C6 lene include ethenylene, propenylene and butenylene. Unless stated ise, C2-C6 alkenylene and C2-C4 alkenylene within the definition of substituents for L, Q1 and Q2, may be unsubstituted or substituted with one or more of the tuents defined herein.
C2-C6 l refers to a linear or branched hydrocarbon chain radical containing at least two carbon atoms and at least one triple bond. Examples of alkenyl groups include ethynyl, propynyl, 2- propynyl, l-butynyl, nyl and l-hexynyl. Unless specified otherwise, C2-C6 alkynyl, within the definitions of Q1 and within the definition of substituents for R6, may be unsubstituted or tuted with one or more of the tuents defined herein.
C1-C6 alkoxy refers to a group or part of a group having an -O-CX_Cy alkyl group according to the definition of CX_Cy alkyl above. C1_C6 alkoxy contains from 1 to 6 carbon atoms and includes C1, C2, C3, C4, C5 and C6. Examples of C1_C6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and hexoxy. Alkoxy as employed herein also extends to embodiments in which the or an oxygen atom (e.g. a single oxygen atom) is located within the alkyl chain, for example CHZCHZOCHg or CH20CH3. Thus the alkoxy may be linked h carbon to the remainder of the molecule, for example, -CH2CH20CH3, or alternatively, the alkoxy is linked through oxygen to the remainder of the molecule, for example -OC1_6 alkyl. In one instances, the alkoxy is linked through oxygen to the der of the molecule but the alkoxy group contains a fithher oxygen atom, for example — OCHZCHZOCHg. Unless specified otherwise, C1-C6 alkoxy and C1-C3 alkoxy within the definitions R13, R", ng, Q1, and within the definition of substituents for R6, may be unsubstituted or substituted with one or more of the tuents defined herein. Examples of substituted C1-C6 alkoxy therefore ll’lClLIdC OCF3, OCHFz, OCH2CF3, CH2CH20CH3 and CH2CH20CH2CH3.
The term "halogen" or "halo" refers to ne, bromine, fluorine or iodine atoms, in particular chlorine or fluorine atoms.
The term "0x0" means =0.
For the avoidance of doubt it will be understood that the lkyl, heterocyclyl, aryl and heteroaryl rings disclosed herein and within the definitions of R13, Rlb, R", R", R15, R", ng, R2, R3, R4, R6, R10, R", R", ring A, and within the definition of substituents for R6, do not include any unstable ring structures or, in the case of heteroaryl and heterocyclic rings systems, any 0-0, 0-8 or 8-8 bonds.
The ring systems may be monocyclic or bicyclic. Bicyclic ring systems include bridged, filSCd and spiro ring systems. A substituent if present may be attached to any suitable ring atom which may be a carbon atom or, in the case of heteroaryl and heterocyclic ring systems, a heteroatom. Substitution on a ring may also include a change in the ring atom at the position of the substitution. For example, substitution on a phenyl ring may include a change in the ring atom at the position of substitution from carbon to nitrogen, resulting in a pyridine ring. "cycloalkyl" refers to a monocyclic saturated or partially unsaturated, non-aromatic ring, wherein all of the ring atoms are carbon, and haVing the number of ring atoms as indicated. For example C3-C10 lkyl refers to a monocyclic or bicyclic hydrocarbon ring containing 3 to 10 carbon atoms.
Examples of C3-C10 lkyl are cyclopropyl, cyclobutyl, entyl, cyclohexyl, cycloheptyl, cyclooctyl and decahydronaphthalenyl. ic cycloalkyl groups e bridged ring systems such as oheptane and bicyclooctane. Unless specified otherwise, cycloalkyl within the definitions of R13, R", R", R", R", R", 111%, R3, R4, R6, R10, R12, R13, and within the definition of substituents for R6, may be unsubstituted or substituted with one or more of the substituents defined herein.
An "aryl" group / moiety refers to any monocyclic or bicyclic hydrocarbon group sing at least one ic group and having from 5 to 10 carbon atom ring members. Examples of aryl groups e phenyl and naphthyl. Bicyclic rings may be filSCd aromatic rings where both rings are aromatic, for example, naphthalenyl. Preferred aryl groups are phenyl and naphthyl, more preferably phenyl. Unless specified otherwise, aryl within the definitions of R3, R4, R6, R10, R", R", ring A and within the definition of substituents for R6, may be unsubstituted or substituted with one or more of the substituents defined herein.
"Heteroaryl" as used herein means a polyunsaturated, clic or bicyclic 5 to 10 membered aromatic moiety containing at least one and up to 5 heteroatoms, particularly 1, 2 or 3 atoms selected from N, O and S, and the remaining ring atoms are carbon atoms, in stable combinations known to the skilled person. aryl ring nitrogen and sulphur atoms are optionally oxidised, and the nitrogen atom(s) are optionally quatemized. A heteroaryl ring can be a single aromatic ring or a filSCd bicyclic ring where the bicyclic ring system can be aromatic, or one of the filSCd rings is aromatic and the other is at least partially saturated. In one e, a bicyclic heteroaryl is one in which the entire filSCd ring system is aromatic. Examples of filSCd rings where one of the rings is aromatic and the other is at least partially saturated include tetrahydropyroidopyrazinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. In such instances, ment of the bicyclic ring to the group it is a substituent of relative to the cyanopyrrolidine core, e.g. N(R2) Via L, is from the aromatic ring of the bicycle. A bicyclic heteroaryl can have the at least one heteroatom in either of the filSCd rings. For example, a bicyclic ring with an aromatic ring filSCd to a partially saturated ring may contain the at least one heteroatom in the ic ring or the partially saturated ring.
Attachment of the bicyclic ring to the group it is a substituent of may be Via either a heteroatom containing ring or a carbon only containing ring. The point of ment of aryl to the group it is a substituent of can be Via a carbon atom or a heteroatom (e.g. nitrogen). In instances where ring A is a heteroaryl, the ring is an aromatic ring and may be filSCd to a fithher aromatic or lly saturated ring. Examples of heteroaryl rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, l, indolizinyl, isoindolyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, azolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofiJranyl, benzothiophenyl, isobenzothiophenyl, idazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, triazinyl, dihydrophyridinyl, dihydropyrrolopyridinyl, isoindolinyl, benzoxazolyl, quinoxalinyl, benzomorpholinyl, tetrahydropyridopyrazinyl, tetrahydroqinolinyl and tetrahydroisoquinolinyl. Unless specified otherwise, heteroaryl within the definitions of R3, R4, R6, R10, R", R", ring A, and within the definition of substituents for R6, may be unsubstituted or substituted with one or more of the substituents d herein.
"Heterocyclyl" or "heterocyclic" as used herein in describing a ring means, unless otherwise stated, a monocyclic ted or partially unsaturated, omatic ring or a bicyclic saturated or partially unsaturated ring, wherein the bicyclic ring system is non-aromatic, the mono- or bicyclic ring having, for example, 3 to 10 members or 5 to 10 members, where at least one member and up to 5 members, particularly 1, 2 or 3 members of the ring are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms, in stable combinations known to those of skill in the art. For example, R2 and R3 may together form a 5 to 7 membered heterocyclic ring which incorporates the amine nitrogen. Heterocyclic ring nitrogen and sulphur atoms are optionally oxidised, and the nitrogen atoms(s) are optionally quatemized. As used herein, the heterocyclic ring may be a filSCd ring to another ring system to form a bicycle, i.e. one or two of the heterocyclic ring carbons is common to an additional ring system. In instances where the heterocylcyl is a bicyclic ring, the second ring can be aromatic, e.g. a filSCd phenyl, pyridyl, pyrazolyl, or the like. The ic heterocyclyl can have at least one heteroatom in either of the filSCd rings. The heterocyclyl may be linked through carbon or a heteroatom to the remainder of the molecule and in instances where the heterocylyl is a ic ring, the link may be Via the heteroatom containing ring or the fiJsed ring. In instances where the cyclyl is a bicyclic ring where the second ring is aromatic, attachment of the bicyclic group to the group it is a tuent of relative to the cyanopyrrolidine core is from the omatic ring. Examples of cyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiiranyl (e. g. 2,3-dihydrofi1ranyl, 2,5-dihydrofi1ranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, lidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, ydroquinolinyl, benzomorpholinyl and tetrahydroisoquinolinyl. Unless specified otherwise, heterocyclyl within the definitions of R", R2, R3, R4, R6, R10, R", R", and within the definition of substituents for R6, may be unsubstituted or substituted with one or more of the substituents defined herein. Examples of substituted heterocyclyl rings include 4,5-dihydro-lH- maleimido, tetramethylenesulfoxide and oinyl.
"Optionally substituted" as applied to any group means that the said group may if desired be tuted with one or more substituents (e.g., l, 2, 3 or 4 substituents) which may be the same or different.
Examples of suitable substituents for "substituted" and "optionally substituted" C1-C6 alkyl (including C1-C4 alkyl, C1-C3 alkyl and C1-C2 alkyl) and C1-C6 alkoxy (including C1-C4 alkoxy, C1-C3 alkoxy and C1-C2 alkoxy) and C2-C6 alkenyl (including C2-C4 alkenyl) and C2-C6 alkynyl (including C2-C4 alkynyl), for example within the definitions of R13, Rlb, R", R", R15, R", ng, R2, R3, R4, R5, R7, R8, R9, R10, R", R", Q, and within the definition of substituents for R6, and C1-C6 alkylene (including C1-C3 alkylene) and C2-C6 alkenylene, for example within the definitions of R5, R7, R8, R9, L, Q1 and Q2, e halogen, hydroxyl, thiol, cyano, amino, nitro and SF5 (a known c of nitro), in particular, halogen (preferably fluorine or ne), hydroxyl and cyano.
Examples of suitable substituents for "substituted" and "optionally substituted" rings, i.e. cycloalkyl, heterocyclyl, aryl and heteroaryl rings, for example within the definitions of R13, Rlb, R", R", R15, R", ng, R2, R3, R4, R6, R10, R", R", and within the definition of substituents for R6, include halogen, cyano, oxo, nitro, amino, amide, y, C1-C6 alkyl or C1-C3 alkyl, C1-C6 alkoxy or C1-C3 alkoxy, aryl, aryl, heterocyclyl, C3-C6 cycloalkyl, C1_3 alkylamino, C2_6 alkenylamino, di-C 1-C3 alkylamino, C1-C3 acylamino, dl'Cl'C3 acylamino, carboxy, C1-C3 alkoxycarbonyl, carboxamidyl, mono-CH carbamoyl, di-C1_3 carbamoyl or any of the above in which a hydrocarbyl moiety is itself substituted by halogen, in particular fluorine, hydroxyl, cyano, amino, nitro or SF5 (a known mimetic of nitro). In groups containing an oxygen atom such as hydroxy and alkoxy, the oxygen atom can be replaced with r to make groups such as thio (SH) and thio-alkyl (S-alkyl). Optional substituents therefore include groups such as S-methyl. In thio-alkyl groups, the sulphur atom may be fithher oxidised to make a sulfoxide or e, and thus optional substituents therefore includes groups such as S(O)-alkyl and alkyl.
Examples of le substituents for ituted" and "optionally substituted" rings include in particular, halogen, oxo, cyano, C1-C3 alkyl, C1-C3 alkoxy, heterocyclyl, lkyl, heteroary or aryl, wherein the alkyl or alkoxy is optionally substituted with one or more (e.g. one, two or three) substituents selected from n, hydroxyl, thiol, cyano, amino, nitro and SF5. In particular, suitable substituents for "substituted" and "optionally substituted" rings disclosed herein include fluorine, chlorine, oxo, cyano, C1-C3 alkyl, C1-C3 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more (e.g. one, two or three) substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular, one or more fluorine. tuted groups thus include for example Br, Cl, F, CN, Me, Et, Pr, Bu, i-Bu, OMe, OEt, OPr, C(CH3)3, )2, CF3, OCF3, C(O)NHCH3, cyclopropyl, phenyl, etc. In the case of aryl groups, the substitutions may be in the form of rings from adjacent carbon atoms in the aryl ring, for example cyclic acetals such as O-CHz-O.
The term "treat" or "treating" or "treatment" includes prophylaxis and means to ameliorate, alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or ion. The compounds ofthe invention are usefiil in the treatment of humans and non-human animals.
The dose of the compound is that amount effective to t occurrence of the ms of the disorder or to treat some symptoms of the disorder from which the patient suffers. By "effective amount" or "therapeutically effective amount" or "effective dose" is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder. Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder to a medically significant extent. Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the er.
Pharmaceutically acceptable salts of the compounds of the invention include but are not limited to addition salts (for example phosphates, nitrates, sulphates, borates, es, maleates, citrates, tes, succinates, methanesulphonates, benzoates, salicylates and hydrohalides), salts derived from organic bases (such as lithium, potassium and sodium), salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, ne, methionine and proline), inorganic bases (such as ylamine, hydroxide, choline, thiamine and N-N’-diacetylethylenediamine). Other pharmaceutically acceptable salts include ammonium salts, tuted ammonium salts and aluminium salts. Further pharmaceutically acceptable salts include quaternary ammonium salts of the nds of the invention.
General methods for the production of salts are well known to the person skilled in the art. 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, ally 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 e using a suitable ion exchange resin.
Where compounds of the invention exist in different enantiomeric and/or diastereoisomeric forms, the invention relates to these compounds prepared as isomeric mixtures or tes whether present in an optically pure form or as mixtures with other isomers. Enantiomers differ only in their ability to rotate plane-polarized light by equal amounts in opposite ions and are denoted as the (+) / (S) or (-) / (R) forms respectively. Individual enantiomers or isomers may be prepared by methods known in the art, such as optical resolution of ts or intermediates (for example chiral tographic separation e.g. chiral HPLC, or an asymmetric synthesis approach). Similarly where compounds of the invention exist as alternative tautomeric forms e.g. keto/enol, amide/imidic acid, the invention relates to the individual tautomers in isolation, and to es of the tautomers in all proportions.
Isotopes The compounds described herein may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the t. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). rly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 180. es of isotopes e 2H, 3H, "C, 13C, 14C,36C1, 18F, 1231, 1251, 13N, 15N, 150, 170, 180,321) and 35s.
In an analogous manner, a reference to a particular fiinctional group also includes within its scope isotopic variations, unless the t indicates otherwise. For example, a reference to an alkyl group such as an ethyl group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group).
The isotopes may be radioactive or non-radioactive. In one embodiment, the compounds contain no radioactive isotopes. Such compounds are red for therapeutic use. In another embodiment, however, the compounds may contain one or more radioisotopes. Compounds containing such sotopes may be usefiil in a diagnostic context.
Certain isotopically ed nds of formula (I), for example, those incorporating a radioactive e, are usefiil in drug and/or substrate tissue distribution studies. The radioactive isotopes i.e. 3H and 14C are particularly usefiil for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in viva half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron on Topography (PET) s for examining receptor occupancy. Isotopically labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using an appropriate isotopically labelled reagent in place ofthe non-labelled reagent previously employed.
Crystalline and amorphous forms The nds of formula (I) may exist in lline or amorphous form and some of the crystalline forms may exist as polymorphs, which are included within the scope of the present invention.
Polymorphic forms of compounds of formula (I) may be characterised and differentiated using a number of conventional analytical techniques, ing, but not limited to, red a, Raman spectra, X-ray powder ction, differential scanning calorimetry, thermogravimetric analysis and solid state nuclear magnetic resonance.
Accordingly, in fithher embodiments, the invention provides a compound according to any described embodiments in a crystalline form. The compound may be from 50% to 100% crystalline, and more particularly is at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% lline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example 100% crystalline. The compound may alternatively be in an amorphous form.
The invention described herein relates to all crystal forms, solvates and hydrates of any of the sed compounds however so prepared. To the extent that any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are ed herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt.
The invention relates to 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 nds of the invention of molecules of a non-toxic pharmaceutically acceptable t (referred to below as the solvating t). 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 t or mixture of solvents containing the solvating solvent. r 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 rd techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
The solvates can be stoichiometric or non-stoichiometric solvates. Particular es may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the s used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc ofWest Lafayette, IN, USA, 1999, ISBN 006710-3.
The invention relates to pharmaceutically fiinctional derivatives of compounds as defined herein including ester derivatives and/or derivatives that have, or provide for, the same biological fimction and/or activity as any relevant compound of the invention. Thus, for the es of this invention, the term also includes prodrugs of compounds as defined herein.
The term "prodrug" of a relevant nd includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an mentally-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).
Prodrugs of nds may be prepared by modifying fiinctional groups present on the compound in such a way that the ations are cleaved, in vivo when such prodrug is administered to a ian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds wherein a hydroxyl, amino, sulflqydryl, yl or carbonyl group in a compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfllydryl, carboxyl or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl onal groups, ester groups of carboxyl fiinctional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in aard, H. "Design of Prodrugs" p. 1-92, Elsevier, New xford (1985).
Compounds of the invention may be metabolised in vivo. Metabolites of compounds of formula (I) are also within the scope of the present invention. The term ‘metabolites’ refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammal. Preferably the term relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions.
A treatment defined herein may be applied as a sole y of may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Furthermore, nds of formula (I) can also be used in combination with eXisting therapeutic agents for the ent of conditions ated with cancer, including small molecule therapeutics or antibody based therapeutics.
The compounds described herein are characterised by a cyanopyrrolidine core with a methylamine group attached to the cyanopyrrolidine ring, wherein the methylamine group is substituted with a monocyclic heteroaryl or aryl ring, wherein the monocyclic heteroaryl or aryl ring is substituted, or an optionally tuted bicyclic heteroaryl or aryl ring, optionally via a linker.
In ance with a first aspect of the invention there is ed a compound of formula (I) or a pharrnaceutically acceptable salt thereof, wherein: Rlb, R", R", R13 each independently represent hydrogen or an optionally substituted C1-C6 alkyl, or R1b is linked to Rla or R1‘: to form an optionally substituted 3 to 6 membered cycloalkyl ring, or R15 is linked to R1d or R" to form an optionally substituted 3 to 6 membered cycloalkyl ring, Rla and ng each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, or Rla and ng together form an optionally substituted C3-C6 lkyl ring, or Rla is linked to R1b to form an optionally substituted C3-C6 cycloalkyl ring, or ng is linked to R" to form an ally substituted C3-C6 cycloalkyl ring, R" represents hydrogen, fluorine, cyano, hydroxyl, amino, ally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R" is linked to ng or R15 to form an optionally substituted 3 to 6 membered cycloalkyl ring, or R" together with R2 forms an optionally fithher tuted heterocyclic ring, R2 represents hydrogen, optionally substituted C1-C6 alkyl or R2 together with R1f forms an optionally fithher substituted heterocyclic ring, X is R4), wherein R3 and R4 each independently represent hydrogen, cyano, optionally substituted C1-C6 alkyl, a 5 or 6 ed heteroaryl or aryl ring or R3 and R4 together form a 3 to 6 membered heteroalkyl or lkyl ring, L represents a covalent bond, -SO-, -SOz-, -C(O)-, -C(O)O-, -CONR5-, -SOZNR5-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C2-C6 alkenylene-C(O)-, -C1-C6 alkylene- NR5C0-, -C1-C6 ne-CONR5-, optionally substituted C1-C6 alkylene or optionally substituted - C2-C6 alkenylene, A represents a substituted monocyclic heteroaryl or aryl ring or an optionally substituted bicyclic heteroaryl or aryl ring, R5 represents en or optionally substituted C1-C6 alkyl.
Rla represents hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 . Rla may represent hydrogen. Rla may represent fluorine. Rla may represent methyl. When Rla represents fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, Rlb, R", R", R15, R" and ng may each represent hydrogen. The alkyl or alkoxy may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.
Alternatively, Rla may be linked to R1b or ng to form an ally substituted cycloalkyl ring. The cycloalkyl ring can contain 3, 4, 5 or 6 atoms, in particular 3 or 4 atoms. The C3-C6 cycolalkyl ring may be substituted or unsubstituted.
Rlb, R", R", R13 may each independently represent en or optionally tuted C1-C6 alkyl. In ular, Rlb, R", R", R15 may each independently represent hydrogen or C1-C3 alkyl (e.g. methyl or ethyl). R1b may be hydrogen or C1-C3 alkyl and R1‘: may be hydrogen. R1d may be hydrogen or C1-C3 alkyl and R15 may be hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. In particular Rlb, R", R", R13 each represent hydrogen.
R1b may represent hydrogen. R1b may ent C1-C6 alkyl. R1b may represent C1-C3 alkyl, for example, methyl or ethyl. When R1b represents C1-C6 alkyl, R13, R", R", R15, R" and ng may each represent hydrogen. The alkyl may be tituted or substituted with one or more substituents ed from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.
R1c may represent hydrogen. R1c may represent C1-C6 alkyl. R1c may represent C1-C3 alkyl, for example, methyl or ethyl. When R1‘: represents C1-C6 alkyl, R", Rlb, Rm, R15, R" and ng may each ent hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents ed from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.
R1d may represent hydrogen. R1d may represent C1-C6 alkyl. R1d may represent C1-C3 alkyl, for example, methyl or ethyl. When R1d represents C1-C6 alkyl, R", Rlb, RIC, R15, R" and ng may each represent hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.
R15 may represent hydrogen. R15 may represent C1-C6 alkyl. R15 may represent C1-C3 alkyl, for example, methyl or ethyl. When R1": ents C1-C6 alkyl, R", Rlb, R", R", R" and ng may each represent hydrogen. The alkyl may be tituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.
Alternatively, R1b may be linked to R1‘: to form a cycloalkyl ring. In addition, or alternatively, R1d may be linked to R15 to form a cycloalkyl ring. The cycloalkyl ring can contain 3, 4, 5 or 6 atoms, in particular 3 or 4 atoms. When R1b and R1‘: together form a C3-C6 cycloalkyl ring, R13, R", R15, R" and ng may be hydrogen. When R1d and R15 together form a cycloalkyl ring, R", Rlb, R", R" and ng may be hydrogen. The cycloalkyl ring may be substituted or unsubstituted. le may represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy. The alkyl and alkoxy may be substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. In particular, R" can represent hydrogen, fluorine, C1-C3 alkyl or substituted C1-C3 alkoxy. R" can represent fluorine. R1f can represent methyl. R1f can represent methoxy. R1f can represent CF3. R" can represent OCF3. In particular examples, le represents hydrogen. ng represents hydrogen, fluorine, cyano, yl, amino, optionally substituted C1-C6 alkyl or ally substituted C1-C6 alkoxy. ng may represent hydrogen. ng may represent e. ng may represent methyl. When ng ents fluorine, cyano, hydroxyl, amino, optionally tuted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, R13, Rlb, R", R", R15 and R1f may each represent hydrogen. The alkyl or alkoxy may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.
Alternatively, ng is linked to Rla or R" to form an optionally substituted lkyl ring. The cycloalkyl ring can contain 3, 4, 5 or 6 atoms, in particular 3 or 4 atoms. When ng forms a C3-C6 cycloalkyl ring, Rlb, R", R", R16 and Rla/R1f may each represent hydrogen. The cycloalkyl ring may be tituted or tuted.
One of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen, and the remaining are each hydrogen.
Two of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen, and the remaining are each hydrogen.
Three of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen, and the remaining are each hydrogen.
Four of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen, and the remaining are each Five of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen, and the remaining are each Six of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen, and the ing are each hydrogen.
When one, two, three, four, five or siX of R", Rlb, R", R", R15, R" and ng are other than hydrogen, the remaining R groups represent a group in accordance with the definitions above. In particular, one, two, three or four of R", Rlb, R", R", R15, R" and ng may be other than hydrogen and the remaining each represent hydrogen. More particularly, one or two of R13, Rlb, R", R", R15, R" and ng may be other than hydrogen and the remaining each ent hydrogen.
The com ounds map y be in the form where R", Rlb, R", R", R15, R" and ng are all hydrogen. In such cases the compounds may be of formula (IA): x‘ "x. , x - . M, z \\ r ,.\_ .xr ’- 3:" €3.- \ l a l ‘s —ss, I’ (K \ .‘ R2 represents hydrogen, C1-C6 alkyl or R2 together with R" forms an optionally fithher substituted heterocyclic ring, n the alkyl may be substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. In particular, R2 represents hydrogen, C1-C3 alkyl, or together with R" forms an ally fithher substituted (i.e. in addition to substitution with —L-A) 5 or 6 membered heterocyclic ring. R2 may represent hydrogen. R2 may represent methyl or ethyl, in ular, methyl. R2 cannot link to R3, R4, L or ring A.
In particular examples, le represents hydrogen and R2 represents hydrogen or C1-C3 alkyl, ably methyl, or R1f and R2 together form a 5 to 7 membered heterocyclic ring (which includes in the ring the amine nitrogen and X), wherein the ring is optionally fithher substituted with one or more fluorine, oxo, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl or alkoxy may be substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. When R1f and R2 together form an ally fithher substituted 5 to 7 ed heterocyclyl ring, this ring is filSCd to the pyrrolidine ring to form an 8 to 10 membered bicyclic ring.
In particular, R" and R2 may together form a 5 membered heterocyclic ring which is not fithher substituted. Alternatively, R" and R2 together form a 5 membered heterocylic ring which is fithher substituted with one or more halogen, oxo, amino, amide, C1-C6 alkyl or C1-C6 alkoxy. In particular, the 5 membered heterocyclyl ring is fithher substituted with oxo. Any fithher substitution is in on to the substitution with ring A, Via L.
In certain instances, R13, Rlb, R", R", R15 and ng may each be en and R" may be hydrogen or er with R2 may form an optionally fithher tuted 5 membered heterocyclyl ring.
X represents C(R3)(R4), wherein R3 and R4 each independently represent hydrogen, cyano, C1-C6 alkyl, an optionally substituted 5 or 6 ed heteroaryl or aryl ring or R3 and R4 together with the carbon to which they are attached form an optionally substituted 3 to 6 membered heterocyclyl or cycloalkyl ring, wherein the alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. The 3 to 6 membered heterocyclyl or cycloalkyl ring may be cyclopropyl or cyclobutyl. In particular, R3 may represent hydrogen and R4 may represent hydrogen, cyano, C1-C6 alkyl, an optionally substituted 5 or 6 membered aryl or aryl ring or R3 and R4 together with the carbon to which they are attached form an optionally substituted 3 to 6 membered heterocyclyl or cycloalkyl ring, wherein the alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. R3 and R4 may each ndently ent hydrogen, cyano, or C1-C3 alkyl. In particular examples, R3 and R4 each independently represent hydrogen, cyano or methyl, e.g.
R3 is hydrogen and R4 is hydrogen, cyano or methyl. More particularly, X represents CH2, CHCN or CHMe.
L represents a covalent bond, -SO-, -SOz-, -C(O)-, -, -CONR5-, -SOZNR5-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C2-C6 alkenylene-C(O)-, -C1-C6 alkylene- NR5C0-, -C1-C6 alkylene-CONR5-, optionally substituted C1-C6 ne or optionally substituted - C2-C6 alkenylene. The alkylene and alkenylene are optionally substituted with halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. R5 represents hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with n, hydroxyl, thiol, cyano, amino, nitro and SF5.
In particular examples, L represents a covalent bond, -SOz-, -C(O)-, -C(O)-C1-C6 alkylene preferably —C(O)-C1-C3 alkylene, -C(O)-C2-C6 alkenylene preferably —C(O)-C2-C4 alkenylene, or - wherein R5 ents hydrogen or methyl, preferably hydrogen.
In formula (I) defined herein, ring A represents a 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered) ring, wherein the ring is either a substituted monocyclic heteroaryl or aryl ring or an optionally substituted bicyclic heteroaryl or aryl ring. The aryl or aryl ring may be attached directly to the amine nitrogen atom to form an N—aryl bond or may be attached via a , i.e. when L is not a nt bond.
When the ring is bicyclic, the second ring (i.e. the ring not attached to the amine nitrogen, either directly or via a linker) may be aromatic or partly unsaturated and thus whilst not every atom in the 5 to 10 heteroaryl or aryl ring need be in an aryl system, there must be at least one aryl or heteroaryl ring within the 5 to 10 atoms, and it is this aryl or heteroaryl ring which is attached to the amine en, either directly or via a linker.
Ring A may represent a 5 to 10 membered heteroary or aryl ring and when tuted, may be substituted with one or more (e.g. one, two, three or four) of —Q1-(R6)n, in particular one or two of Q1- (R6)n.
In particular, ring A may ent a 5 or 6 membered heteroaryl or aryl ring which is substituted with one or more (e.g. one, two, three or four) of —Q1-(R6)n.
Alternatively, ring A may ent a 9 or 10 membered bicyclic heteroaryl or aryl ring which may be optionally substituted with one or more (e.g. one, two, three or four) of —Q1-(R6)n.
When ring A is a heteroaryl ring, the ring may comprise one or more (e.g. l, 2 or 3) atoms independently selected from nitrogen, oxygen and sulphur. In particular, the heteroaryl ring contains at least one nitrogen atom, for example, 1, 2 or 3 nitrogen atoms, preferably 1 or 2 nitrogen atoms.
Ring A may be selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, lyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, iranyl, isobenzofiJranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, triazinyl, dihydrophyridinyl, dihydropyrrolopyridinyl, benzoxazolyl, alinyl, benzomorpholinyl, tetrahydropyridopyrazinyl, tetrahydroqinolinyl, tetrahydroisoquinolinyl, isoindolinyl, phenyl, naphthyl and naphthalenyl.
In particular, ring A is selected from the group ting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofiJranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, inyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, benzomorpholinyl, phenyl, naphthyl and naphthalenyl.
More particularly, ring A is selected from the group consisting of oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl, inyl, benzothiazolyl, isoquinolinyl, pyrimidinyl, phenyl, benzomorpholinyl, indazolyl, imidazopyridinyl, quinazolinyl, pyrazolopyridinyl, benzimidazolyl, imidazolyl and oxadiazolyl.
For example, ring A is selected from the group consisting of yl, isoxazolyl, pyrazolyl, thiazolyl, nyl, quinolinyl, benzothiazolyl, isoquinolinyl, pyrimidinyl, phenyl, benzomorpholinyl, indazolyl, imidazopyridinyl, and olinyl.
When ring A is monocyclic the ring is substituted. When ring A is bicyclic the ring may be either unsubstituted or substituted. When substituted, ring A may be substituted with one or more -Q1-(R6)n, in particular one or two -Q1-(R6)n, wherein each occurrence -Q1-(R6)11 is the same or different, and wherein: n is 0 or 1, Q1 represents halogen, cyano, oxo, nitro, -OR7, -SR7, -NR7R8, -CONR7R8, -NR7COR8, - NR7CONR8R9, -COR7, R7, -sozR7, 7R8, -NR7SOZR8, NR8R9, -NR7C(O)OR8, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally tuted —C2-C6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -SO- , -soz-, -C(O)-, -C(O)O-, -CONR7-, -NR7-, -, NR8-, -SOZNR7-, -NR7SOZ-, NR7SOZNR8-, -NR7C(O)O-, -NR7C(O)OR8-, optionally substituted C1-C6 alkylene or optionally substituted -C2-C6 alkenylene, R7, R8 and R9 each independently represent hydrogen, optionally substituted C1-C6 alkyl or ally substituted C1-C6 alkylene.
When n is l, R6 represents an optionally substituted 3 to 10 membered cyclyl, cycloalkyl, heteroaryl or aryl ring (when n is 0, Q1 is present and R6 is absent).
Ring A may be unsubstituted (if a bicyclic ring) or substituted with one, two, three or four of -Q1- (R6)n. In particular, ring A is either unsubstituted (if a bicyclic ring) or substituted with one or two of -Q1-(R6)n. Each occurrence of -Q1-(R6)11 may be the same or different. More particularly, ring A is either unsubstituted (if bicyclic) or substituted with one of Ql-(R6)n. Q, R6 and n are as defined herein.
In particular, Q1 may be selected from halogen (e.g. e, ne or bromine), cyano, oxo, nitro, - OR7 (e.g yl), -SR7 (e.g. , -NR7R8 (e.g. amino or N,N—dimethylamino), -CONR7R8 (e.g. amido), R8 (N—acetyl), -NR7CONR8R9, -COR7 (e.g. ), -C(O)OR7 (e.g. methoxycarbonyl or ethoxycarbonyl), -SOZR7 (e.g. methyl sulphonyl), -SOZNR7R8 (e.g. dimethylaminosulphonyl), - NR7SOZR8, NR7SOZNR8R9, -NR7C(O)OR8, optionally substituted -C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl), optionally substituted C1-C2 alkyl (e. g. methyl or eithyl), optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, -C(O)O-, -CONR7-, -NR7- (e.g. methylamino), - NR7CO-, -NR7CONR8-, -SOZNR7-, -NR7SOZ-, -NR7SOZNR8-, -NR7C(O)O-, -NR7C(O)OR8-, optionally substituted C1-C4 ne (e.g. methylene or ne) or optionally substituted -C2-C4 alkenylene (e,g. Vinyl).
When n is 0, ring A may be tuted with one or more (e.g. one, two, three or four) Q1 substituents independently selected from halogen (e.g. fluorine, chlorine or bromine), cyano, oxo, nitro, -OR7, - SR7, -NR7R8, -CONR7R8, -NR7C(O)R8, O)NR8R9, -C(O)R7, -C(O)OR7, -sozR7, -SOZNR7R8, - NR7SOZR8, NR7SOZNR8R9, -NR7C(O)OR8, -C1-C6 alkyl, -C1-C6 alkoxy,—C2-C6 alkenyl, or —C2-C6 alkynyl, wherein alkyl, alkoxy, alkenyl or alkynyl, may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, and wherein R7, R8 and R9 are as defined above.
In ular, when n is 0, Q1 may represent halogen (e.g. fluorine or ne), cyano, oxo, - C(O)NR7R8, -NR7COR8, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl and alkoxy may be unsubstituted or substituted with one or more halogen, in particular fluorine.
In particular examples, n is 0 and ring A represents a 5 or 6 membered heteroaryl or aryl ring which is substituted with one or more (e.g. one, two, three or four) Q1 substituents independently selected from halogen, oxo, -NR7COR8, C1-C3 alkyl (e.g. methyl) or C1-C3 alkoxy (e.g. y), wherein the alkyl or alkoxy is optionally substituted with one or more fluorine.
In fithher examples, n is 0 and ring A represents a 9 or 10 membered heteroaryl or aryl ring which is ally substituted with one or more (e.g. one, two, three or four) Q1 substituents independently selected from halogen, oxo, cyano, C1-C3 alkyl or -C(O)NR7R8, wherein the alkyl is optionally substituted with one or more fluorine.
When n is 1, Q1 is a covalent bond or a linker selected from an oxygen atom, a sulphur atom, -SO-, - 802-, -CO-, -C(O)O-, -CONR7-, -NR7-, -NR7CO-, -NR7CONR8-, 7-, -NR7SOZ-, -NR7SOZNR8- , -NR7C(O)O-, -NR7C(O)OR8-, C1-C6 alkylene or -C2-C6 alkenylene, wherein the alkylene or alkenylene is optionally substituted with one or more tuents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.
In particular, when n is 1, Q1 is ed from a covalent bond, C1-C6 alkylene in ular C1-C3 alkylene, preferably ene, or an oxygen atom.
In particular examples, ring A is substituted with a further ring either directly or Via a , i.e., ring A is substituted with at least one -Q1-(R6)11 wherein n is 1.
R6 represents a 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring. R6 may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, , naphthyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, zinyl, isoindolyl, indolinyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofuranyl, benzothiophenyl, zothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, lopyridinyl, triazinyl, dihydrophyridinyl, dihydropyrrolopyridinyl, benzoxazole, alinyl, benzomorpholinyl, tetrahydropyridopyrazinyl, inyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiiranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g. 3,4- dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, linyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, ydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
R6 may be ed from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, inyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, orpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiiranyl (eg. 2,3-dihydrofi1ranyl, 2,5-dihydrofi1ranyl), anyl, morpholinyl, idinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, rpholinyl, dihydropyranyl (eg. 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
R6 may represent an optionally substituted 5 or 6 membered cyclyl, cycloalkyl, heteroaryl or aryl ring.
Alternatively, R6 may represent an optionally substituted 9 or 10 ed bicyclic heterocyclyl, cycloalkyl, aryl or aryl ring.
In particular, R6 is selected from substituted or tituted phenyl, thiazolyl, nyl, pyrrolidinyl pyrazolyl, isoindolyl, isoxazolyl and cycloalkyl, e.g. cyclopropyl or cyclobutyl.
More particularly, R6 is selected from substituted or unsubstituted phenyl, thiazolyl, pyridinyl, idinyl pyrazolyl, isoindolyl, isoxazolyl and cyclopropyl.
For example, R6 is selected from substituted or unsubstituted phenyl, thiazolyl, pyridinyl, pyrrolidinyl, pyrazolyl and isoindolyl.
More particularly, R6 is substituted or unsubstituted phenyl.
In all cases described herein, R6 may be optionally tuted with one or more substituents independently selected from halogen, cyano, oxo, nitro, -OR10, -SR10, -NR10R", -CONR10R", - NRIOCOR", ONR"R12, -COR10, R1°, -SOZR10, -SOZNR1°R", -NR1°SOZR", NRmSOzNRURu, -NR10C(O)OR", optionally substituted -C1-C6 alkyl, ally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted -C2-C6 alkynyl, -Q2-R10, -Q2- NRIOCONRUR", -Q2-NR1°R", -Q2-COR1°, -Q2-NR1°COR", 10C(O)OR", -Q2-SOZR10, Q2- CONRlOR", -Q2-C02R10, -Q2-SOZNR1°R", —Q2-NR1°SOZR" and -Q2-NR1°SOZNR"R12, wherein the alkyl, alkoxy, alkenyl or alkynyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.
Q2 represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, C1-C6 ne or optionally substituted C2-C6 alkenylene.
R10, R", R12 each independently represent hydrogen, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl.
R6 may be substituted with one or more (e.g. one, two, three or four), in particular one or two, substituents independently selected from halogen, cyano, oxo, nitro, -OR10, -SR10, -NR10R", - CONRlOR", -NR1°C0R", -NR1°CONR"R12, -COR10, R1°, -SOZR10, -SOZNR1°R", - NRIOSOZR", NRmSOZNRURu, -NR10C(O)OR", optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted -C2-C6 l, -Q2-R10, -Q2-NR1°CONR"R12, -Q2-NR1°R", -Q2-COR1°, -Q2-NR10COR", -Q2- NR1°C(0)0R", ZR10, QZ-CONRIOR", -Q2-C02R10, -Q2-SOZNR1°R", —Q2-NR1°SOZR" and - QZ-NRNSOZNRURIZ, wherein Q2 ents a covalent bond, an oxygen atom, a sulphur atom, -SO-, - 802-, -CO-, C1-C6 ne or optionally substituted C2-C6 alkenylene, and wherein R10, R", R12 each independently represent en or optionally substituted C1-C6 alkyl, wherein any alkyl, alkoxy, l, alkynyl, alkylene or alkenylene is optionally tuted with one or more (e.g. one, two, three or four) substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.
In particular, R6 may be substituted with one or more tuents ed from halogen (for example, fluorine or chlorine), cyano, C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl), C1-C4 alkoxy or C1-C2 alkoxy (e. g. methoxy) wherein the alkyl and alkoxy may be optionally substituted with one or more fluorine.
For example, R6 may be substituted with one or more substituents ed from halogen (for example, fluorine or chlorine), C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl) wherein the alkyl may be ally substituted with one or more fluorine.
Alternatively, R6 may be optionally substituted with a fithher optionally substituted 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring, either directly attached or via a linking group. The g group may be an oxygen atom, a carbonyl or an optionally substituted C1-C6 ne. The linking group may be oxygen, -CO- or an alkylene chain, for example, methylene. The 3 to 10 membered ring may be substituted with one or more (e.g. one, two, three of four), in particular one or two, tuents selected from halogen (for example, e or chlorine), C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl) wherein the alkyl may be optionally substituted with one or more fluorine.
R6 may be unsubstituted, mono-substituted or di-substituted.
In certain ces, R6 represents a 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, olyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, flirazanyl, imidazolyl, indazolyl, azolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, dihydropyrrolopyridinyl, benzoxazolyl, quinoxalinyl, benzomorpholinyl, tetrahydropyridopyrazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiiranyl (e.g. hydrofuranyl, 2,5-dihydrofi1ranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, ydropyranyl, ydropyridinyl, tetrahydropyrimidinyl, ydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl and ydroisoquinolinyl which is either unsubstituted or tuted with one or more (e.g. one, two or three) substituents selected from halogen (e.g. fluorine or chlorine), cyano, oxo, nitro, -OR10, -SR10, -NR10R", - CONRlOR", 0R", ONR"R12, -COR10, -C(O)OR1°, -SOZR10, -SOZNR1°R", - NRIOSOZR", NRmSOZNRURu, -NR10C(O)OR", optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally tuted —C2-C6 alkenyl, optionally substituted -C2-C6 alkynyl, -Q2-R10, -Q2-NR1°CONR"R12, -Q2-NR1°R", -Q2-COR1°, -Q2-NR10COR", -Q2- NR1°C(0)0R", -Q2-SOZR10, QZ-CONRIOR", -Q2-C02R10, -Q2-SOZNR1°R", —Q2-NR1°SOZR" and - SOZNRURIZ, wherein the alkyl, , alkenyl or alkynyl are optionally substituted with one or more substituents selected from n, hydroxyl, thiol, cyano, amino, nitro and SF5, wherein Q2 represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, C1-C6 alkylene or optionally substituted C2-C6 alkenylene, and R10, R", R12 each independently represent hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl.
R6 may represent a 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ctyl, decahydronaphthalenyl, phenyl, naphthyl, alenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, azolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofiJranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, opyridinyl, pyrazolopyridinyl, lopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, orpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiiranyl (eg. 2,3-dihydrofuranyl, 2,5-dihydrofiJranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (eg. 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, lidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl which is either tituted or substituted with one or more (e. g. one, two or three) substituents selected from halogen (e. g. fluorine or chlorine), cyano, oxo, nitro, -OR10, -SR10, - NRloR", -C0NR1°R", -NR1°C0R", -NR10CONR"R12, -COR10, -C(O)OR1°, -SOZR10, 1°R", - NRIOSOZR", NRmSOZNRURu, -NR10C(O)OR", optionally tuted -C1-C6 alkyl, ally substituted -C1-C6 , optionally substituted —C2-C6 alkenyl, optionally substituted -C2-C6 alkynyl, -Q2-R10, -Q2-NR1°CONR"R12, -Q2-NR1°R", -Q2-COR1°, -Q2-NR10COR", -Q2- NR1°C(0)0R", -Q2-SOZR10, QZ-CONRIOR", -Q2-C02R10, -Q2-SOZNR1°R", —Q2-NR1°SOZR" and - QZ-NRNSOZNRURIZ, wherein the alkyl, alkoxy, alkenyl or alkynyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, wherein Q2 represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, C1-C6 alkylene or optionally substituted C2-C6 alkenylene, and R10, R", R12 each ndently represent hydrogen, ally substituted C1-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, ally tuted aryl, or an optionally substituted cycloalkyl.
R6 may represent a ring selected from phenyl, thiazolyl, nyl, idinyl pyrazolyl, isoindolyl, isoxazolyl and cycloalkyl, wherein the ring is unsubstituted or substituted with one or more, in particular one or two, substituents selected from halogen (e. g. fluorine or chlorine), cyano, oxo, nitro, -0R1°, -SR1°, -NR1°R", -C0NR1°R", 0R", -NR10CONR"R12, -COR10, -C(O)OR1°, -SOZR10, - SOZNRNR", -NR10802R", NRIOSOZNRHR", -NR1°C(O)OR", optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted -C2- C6 alkynyl, 0, -Q2-NR1°CONR"R12, -Q2-NR10R", -Q2-COR1°, -Q2-NR1°COR", -Q2- NR1°C(0)0R", -Q2-SOZR10, QZ-CONRIOR", -Q2-C02R10, ZNR1°R", —Q2-NR1°SOZR" and - QZ-NRNSOZNRURIZ, wherein the alkyl, alkoxy, alkenyl or alkynyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, wherein Q2 ents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, C1-C6 alkylene or optionally tuted C2-C6 alkenylene, and R10, R", R12 each independently represent hydrogen, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl.
R6 may represent a ring ed from phenyl, lyl, pyridinyl, pyrrolidinyl pyrazolyl, isoindolyl and isoxazolyl, wherein the ring is tituted or substituted with one or more, in particular one or two, tuents selected from halogen (e.g. fluorine or chlorine), cyano, oxo, nitro, -OR10, -SR10, - NRloR", -C0NR1°R", -NR1°C0R", -NR10CONR"R12, -COR10, R1°, -SOZR10, -SOZNR1°R", - NRIOSOZR", NRURu, -NR10C(O)OR", optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted -C2-C6 alkynyl, -Q2-R10, -Q2-NR1°CONR"R12, -Q2-NR1°R", -Q2-COR1°, -Q2-NR10COR", -Q2- NR1°C(0)0R", -Q2-SOZR10, QZ-CONRIOR", -Q2-C02R10, -Q2-SOZNR1°R", —Q2-NR1°SOZR" and - QZ-NRNSOZNRURIZ, wherein the alkyl, alkoxy, alkenyl or alkynyl are optionally substituted with one or more substituents selected from halogen, yl, thiol, cyano, amino, nitro and SF5, wherein Q2 represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, C1-C6 alkylene or optionally substituted C2-C6 alkenylene, and R10, R", R12 each independently ent hydrogen, optionally substituted C1-C6 alkyl, ally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an ally substituted cycloalkyl.
R6 may represent a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, yl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, indolizinyl, olyl, indolinyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, zofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, lopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, dihydropyrrolopyridinyl, benzoxazolyl, alinyl, benzomorpholinyl, tetrahydropyridopyrazinyl, inyl, pyrrolidinyl, piperidinyl, azepanyl, anyl, dihydrofiiranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g. hydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl, wherein the ring is unsubstituted or substituted with one or more (e. g. one, two or three) substituents selected from halogen (for example, fluorine or ne), cyano, C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl), C1-C4 alkoxy or C1-C2 alkoxy (e.g. methoxy) wherein the alkyl and alkoxy may be optionally substituted with one or more fluorine, wherein the alkyl and alkoxy may be optionally tuted with one or more fluorine.
R6 may represent a ring selected from cyclopropyl, cyclobutyl, entyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, olyl, indolyl, indolizinyl, olyl, indolinyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, nyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, orpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiiranyl (e.g. 2,3-dihydrofi1ranyl, 2,5-dihydrofi1ranyl), dioxolanyl, morpholinyl, idinyl, oxazinanyl, indolinyl, olinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), perazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, ydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl, wherein the ring is unsubstituted or substituted with one or more (e. g. one, two or three) substituents selected from halogen (for example, fluorine or chlorine), C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl), wherein the alkyl may be optionally tuted with one or more fluorine, wherein the alkyl and alkoxy may be optionally substituted with one or more fluorine.
In particular, R6 may be selected from phenyl, thiazolyl, pyridinyl, pyrrolidinyl pyrazolyl, isoindolyl isoxazolyl and cyclopropyl, n the ring is unsubstituted or substituted with one or more (e.g. one, two or three) substituents ed from halogen (for example, fluorine or chlorine), cyano, C1-C4 alkyl (e.g. propyl, yl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl), C1-C4 alkoxy or C1-C2 alkoxy (e. g. methoxy), wherein the alkyl and alkoxy may be optionally substituted with one or more fluorine.
For example, R6 may be selected from phenyl, thiazolyl, pyridinyl, pyrrolidinyl pyrazolyl, isoindolyl and olyl, wherein the ring is unsubstituted or tuted with one or more (e.g. one, two or three) substituents selected from halogen (for example, fluorine or chlorine), C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl) or C1-C2 alkyl (e.g. methyl or ethyl), wherein the alkyl may be optionally substituted with one or more fluorine.
The present invention fithher relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Rlb, RIC, R1d and R13 each independently represent C1-C3 alkyl which may be optionally substituted with one or more fluorine; Rla and ng each independently represent hydrogen, fluorine or C1-C3 alkyl which may be ally substituted with one or more fluorine; R" is hydrogen, fluorine, C1-C3 alkyl which may be optionally substituted with one or more e or together with R2 forms a 5 membered cyclic ring which is optionally fithher substituted with fluorine, oxo, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy, R2 is hydrogen or C1-C3 alkyl or together with R1f forms a 5 membered heterocyclic ring which is optionally fithher substituted with fluorine, oxo, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 , X represents C(R3)(R4), wherein R3 and R4 each independently represent hydrogen, cyano or C1-C3 alkyl which may be optionally substituted with one or more halogen, L is a covalent bond, -C(O)-, -SOz-, -CONR5-, -C6 alkylene or -CO-C2-C6 alkenylene wherein R5 represents hydrogen or methyl, A represents a 5 or 6 membered monocyclic heteroaryl or aryl which is substituted with one, two or three of —Q1-(R6)n, or a 9 or 10 membered bicyclic heteroaryl or aryl which is optionally substituted with one, two or three of —Q1-(R6)n, wherein each —Q1-(R6)11 is the same or different, n is 0 or 1, Q, R6 and n are as defined herein.
In ular, Q1 is selected from halogen (e.g. fluorine, chlorine or bromine), cyano, oxo, nitro, -OR7 (e.g hydroxyl), -SR7 (e.g. thiol), -NR7R8 (e.g. amino or N,N—dimethylamino), R8 (e.g. amido), -NR7COR8 (N—acetyl), -NR7CONR8R9, -COR7 (e.g. acetyl), -C(O)OR7 (e.g. ycarbonyl or ethoxycarbonyl), -SOZR7 (e. g. methyl sulphonyl), -SOZNR7R8 (e. g. dimethylaminosulphonyl), - NR7SOZR8, NR7SOZNR8R9, -NR7C(O)OR8, optionally substituted -C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl), optionally substituted C1-C2 alkyl (e.g. methyl or ethyl), optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, -C(O)O-, -CONR7-, -NR7- (e.g. methylamino), - , NR8-, -SOZNR7-, -NR7SOZ-, -NR7SOZNR8-, -NR7C(O)O-, -NR7C(O)OR8-, ally substituted C1-C4 alkylene (e.g. methylene or ethylene) or optionally tuted -C2-C4 alkenylene (e,g. vinyl), and R6 is a 5 or 6 membered heteroaryl, heterocyclyl or aryl ring optionally substituted with one or two substituents ndently selected from halogen, cyano, oxo, nitro, - 0R1", -SR1°, ", -C0NR1°R", -NR1°C0R", -NR10CONR"R12, -COR10, -C(O)OR1°, -SOZR10, - SOZNRNR", -NR10802R", NRIOSOZNRHR", -NR1°C(O)OR", optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally tuted —C2-C6 alkenyl, optionally substituted -C2- C6 alkynyl, -Q2-R10, -Q2-NR1°CONR"R12, -Q2-NR10R", -Q2-COR1°, -Q2-NR1°COR", -Q2- NR1°C(0)0R", -Q2-SOZR10, QZ-CONRIOR", -Q2-C02R10, -Q2-SOZNR1°R", —Q2-NR1°SOZR" and - QZ-NRNSOZNRURIZ, wherein Q2 ents a covalent bond, an oxygen atom, a sulphur atom, -SO-, - 802-, -CO-, C1-C6 alkylene or optionally substituted C2-C6 alkenylene, and wherein R10, R", R12 each independently represent hydrogen or optionally substituted C1-C6 alkyl, wherein any alkyl, alkoxy, alkenyl, alkynyl, alkylene or alkenylene is optionally substituted with one or more (e.g. one, two, three or four) substituents ed from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.
The present invention fithher s to nds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R". Rlb, R", R", R13 and ng are each hydrogen, R" is hydrogen or together with R2 forms a 5 membered heterocyclic ring which is optionally further substituted with one substituent, R2 is hydrogen or methyl or together with R1f forms a 5 membered heterocyclic ring which is ally substituted with one fithher substituent, X ents C(R3)(R4), n R3 ents hydrogen and R4 represent hydrogen, cyano or C1-C3 alkyl, L is a covalent bond, -C(O)-, -SOz-, -CONH-, -CO-C1-C3 alkylene, in particular -C(O)-, -CO- methylene, or -CO-ethenylene, A represents a 5 or 6 membered monocyclic heteroaryl or aryl which is substituted with one or two of —Q1-(R6)n, or a 9 or 10 membered bicyclic heteroaryl or aryl which is unsubstituted or substituted with one or two of —Q1-(R6)n, each occurrence of —Q1-(R6)11 is the same or different, wherein: n is 0 or 1, Q1 represents halogen, in particular e or chlorine, oxo, cyano, -CONR7, -NR7COR8, C1-C3 alkyl optionally substituted with one or more fluorine, for example CF3, -SOZNH-, C1-C3 alkoxy for example methoxy, a covalent bond, an oxygen atom or C1-C3 alkylene for example methylene, R6 represents a 3 to 6 membered heterocyclyl, cylcoalkyl, heteroaryl or aryl ring, in particular, R6 represents phenyl, thiazolyl, pyridinyl, pyrrolidinyl, lyl, olyl, isoxazolyl or cyclopropyl, wherein R6 is unsubstituted or substituted with one or more substituents selected from halogen, cyano, C1-C3 alkyl for example methyl or C1-C3 alkoxy, for e methoxy, R7 and R8 each independently represent hydrogen or C1-C3 alkyl.
The present invention fithher relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R". Rlb, R", R", R13 and ng are each en, R" is hydrogen or together with R2 forms a 5 membered heterocyclic ring which is optionally further substituted with one substituent, R2 is hydrogen or methyl or together with R1f forms a 5 membered heterocyclic ring which is optionally tuted with one r substituent, X represents C(R3)(R4), wherein R3 represents hydrogen and R4 represent hydrogen, cyano or C1-C3 alkyl, L is a covalent bond, , -SOz-, -CONH-, -CO-C1-C3 alkylene, in particular -CO-methylene, or - CO-ethenylene, A represents a 5 or 6 membered monocyclic aryl or aryl which is substituted with one or two of —Q1-(R6)n, or a 9 or 10 membered bicyclic aryl or aryl which is unsubstituted or substituted with one or two of —Q1-(R6)n; each occurrence of —Q1-(R6)11 is the same or different, n: Q1 represents halogen, in particular fluorine or chlorine, oxo, cyano, -CONR7, -NR7COR8, C1-C3 alkyl optionally substituted with one or more fluorine, for example CF3, -SOZNH-, C1-C3 alkoxy for example methoxy, a covalent bond, an oxygen atom or C1-C3 alkylene for example methylene, R6 represents a 5 or 6 membered heterocyclyl, cylcoalkyl, heteroaryl or aryl ring, in particular, R6 represents phenyl, thiazolyl, pyridinyl, pyrrolidinyl or pyrazolyl, wherein R6 is unsubstituted or substituted with one or more substituents selected from halogen or C1-C3 alkyl, for e, methyl, R7 and R8 each independently represent hydrogen or C1-C3 alkyl. es of ring A include those shown below: - r" __v' -\ :3. W3 x. i -\::~»,_ fi. a. x a, t \. s s s \ s s s‘ ' . § § § 5‘ g 1 k ,r 3 , "3 \ 3* , fist" . "a, xi: "MN" \\\»\fi_‘ x-‘cAfl‘Kx_. 4- "x" / xx...» \ "A ’c\’\(\[’r§c\(‘ "Q "‘ (EAR.
I‘T \ ’ "u \\. 'x, ~‘ ..—\-.{ X , Sir" \\ a \, x a" "K .s" "if" b}- .» A"\-\v"x_xx :- ~- .\ r2 . '\ :5 § 3 \ § § : :mf E: .9 ‘f‘ $ § E5 3 3 a g : := = a J 3 -‘ a. 55 ."N sat .. "Km." a) ‘ M. ‘N EM. _:'.f"\ .: \Vx‘x .3 "N. .5' §5,. «g, x, — \. * (z ‘w x .,x‘ _.- w} x MN.- .3 x.‘ a ' V "x..- .N" N5 . ,5" a .-""x v' 9" A", .v ,3? \‘Va "N J w" x». "' v- - .v ‘ .v’" M ’x; . "w" ‘ .-" N xx,» \...— \ \ , x S t x % S E 3 \ 3 \, E \ t \ x x .- \ i\_ i "w r‘ 3 ‘\\:"x "x. 1 ‘ ‘x -’ x w «x .., x 5 \x__»-., ..-. a»): xwf "x 1 , >5 - .- ------------- "K i », I ‘ \ ." ~ ‘3. \ ‘3. ; -. 33:1! \\\'\.
K xx 3‘...
J a: """"\N .i M N N ("Kn ‘ _ \ , m i N-i‘, h ..
N ’ Xx.
"WWW. 4‘ " an.» \3\.:w~" \x‘fifx T .13; o / c-V/‘AIMA wherein ents the point of attachment to the remainder of the molecule, i.e. to the amine nitrogen Via L, and wherein the monocyclic rings are substituted with one or more of —Q1-(R6)11 and wherein the ic rings are optionally substituted with one or more of —Q1-(R6)n. Hydrogen atoms attached to the ring nitrogen atoms have not been shown. It will be understood by the skilled person which ring nitrogen atoms are suitable for substitution and Where not substituted the nitrogen may be bound to a hydrogen atom to complete its valency, Where appropriate.
Examples of novel compounds of a (I) include: 3 -((quinolinylamino)methyl)pyrrolidine- l -carbonitrile 3 -(((6-fluorobenzo [d]thiazolyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -((isoquinolin- l -ylamino)methyl)pyrrolidine- l -carbonitrile 3 -(((3 -phenylpyridinyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -(((4-phenylpyridinyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -(((5 -phenylpyridinyl)amino)methyl)pyrrolidine- l -carbonitrile 3 phenylpyridinyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -(((4-phenylpyrimidinyl)amino)methyl)pyrrolidine- l -carbonitrile (R)-3 -(((5 -phenylthiazolyl)amino)methyl)pyrrolidine- l -carbonitrile (S)-3 -(((5 -phenylthiazolyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -(((6-( lH-pyrazolyl)benzo [d]thiazolyl)amino)methyl)pyrrolidine- l -carbonitrile (R)-3 -(((7-( lH-pyrazolyl)quinazolinyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -(((3 -( l 3 -dimethyl- lH-pyrazolyl)phenyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -(((4-( l 3 -dimethyl- lH-pyrazolyl)phenyl)amino)methyl)pyrrolidine- l -carbonitrile 3 ( l 3 hyl- lH-pyrazolyl)fluorophenyl)amino)methyl)pyrrolidine- l -carbonitrile 3 -((( l -cyanopyrrolidin-3 thyl)amino)isoquinolinecarbonitrile 3 -((( l -cyanopyrrolidin-3 -yl)methyl)amino)-N-methylisoquinolinecarboxamide 3 (isoindolinyl)pyridinyl)amino)methyl)pyrrolidine- l -carbonitrile (S)-3 -(((4-phenylpyrimidinyl)amino)methyl)pyrrolidine- l -carbonitrile \ -(( l -cyanopyrrolidin-3 -yl)methyl)phenyloxazole-5 -carboxamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)-3 -phenylisoxazole-5 -carboxamide \ -(( l -cyanopyrrolidin-3 thyl)-5 -phenyl- lH-pyrazole-3 -carboxamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)methyl-3 -oxo-3 ,4-dihydro-2H-benzo [b] [ l ,4]oxazine carboxamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)(pyridinyl)benzamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)-3 -(o-tolyl)- lH-pyrazole-5 -carboxamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)phenylthiazolecarboxamide \ -(( l -cyanopyrrolidin-3 thyl)(pyrrolidin- l -yl)picolinamide \ -(( l pyrrolidin-3 -yl)methyl)- l -(2,4-dichlorobenzyl) - lH-indazole-3 -carboxamide l-benzyl-N-(( l -cyanopyrrolidin-3 -yl)methyl)- lH-indazole-3 -carboxamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)(N-phenylsulfamoyl)benzamide \ -(( l -cyanopyrrolidin-3 -yl)methyl)-3 -(2-fluorophenyl) - lH-pyrazole-S -carboxamide (E)-N-(( opyrrolidin-3 -yl)methy1)-3 -(2-fluoromethoxyphenyl)acrylamide N—((1-cyanopyrrolidin-3 -yl)methyl)-5 -(4-fluoropheny1)nicotinamide (S)-N-((1-cyanopyrrolidin-3 -y1)methy1)-3 -oxo-3 ,4-dihydro-2H-benzo [b] [ 1 zinecarboxamide (R)chloro-N-((1-cyanopyrrolidin-3 -yl)methyl)imidazo[ 1 ,2—a]pyridinecarboxamide (R)-N-(( 1 pyrrolidin-3 -y1)methy1)pyrazolo[1,5 -a]pyridinecarboxamide 2—([ 1, 1'—bipheny1]—4-y1)-N-((1-cyanopyrrolidin-3 -yl)methyl)-N-methylacetamide N-((1-cyanopyrrolidin-3 -y1)methy1)-5 -phenyloxazolecarboxamide N—((1-cyanopyrrolidin-3 -yl)methyl)( 1 -methyl- 1H-pyrazoly1)imidazo[ 1 ,2—a]pyridine amide 1-benzy1-N-((1 -cyanopyrrolidin-3 -yl)methy1)-5 -methy1-1H-pyrazole-3 -carboxamide 1-(3 -chlorophenyl)-3 -((1-cyanopyrrolidin-3 -yl)methyl)urea 1-((1-cyanopyrrolidin-3 -yl)methy1)-3 -(2-fluoro-5 -methylphenyl)urea 1-(3 1pheny1)-3 -((1-cyanopyrrolidin-3 thyl)urea 1-((1-cyanopyrrolidin-3 -yl)methy1)-3 -(2,4-dichlorophenyl)urea 1-((1-cyanopyrrolidin-3 thy1)-3 -(4-(trifluoromethyl)phenyl)urea N—((1-cyanopyrrolidin-3 -yl)methyl)-N-methyl-3 -(2-methylthiazoly1)benzenesulfonamide N—((1-cyanopyrrolidin-3 -yl)methy1)-N-methyl((5 -(trifluoromethyl)pyridin yl)oxy)benzenesulfonamide 3 -(1-((6-(5 -methy1isoxazoly1)benzo[d]thiazolyl)amino)ethy1)pyrrolidine-l-carbonitrile 3 -(1-((6-(1H-pyrazolyl)benzo[d]thiazoly1)amino)ethyl)pyrrolidinecarbonitrile 3 -(1-(isoquinolin-3 -y1amino)ethyl)pyrrolidinecarbonitri1e 3 -((1-(1-cyanopyrrolidin-3 -y1)ethyl)amino)isoquinolinecarbonitrile 3 -((benzo [d]thiazoly1amino)(cyano)methyl)pyrrolidine- 1 nitri1e 2-((1-(1-cyanopyrrolidin-3 -y1)ethy1)amino)benzo [d]thiazolecarbonitrile (3aR,6aS)0X0-5 -(5 -pheny1thiazoly1)hexahydropyrrolo [3 ,4-c]pyrrole-2(1H)-carbonitrile (R)-3 -(3 -chloropheny1)-N-((1-cyanopyrrolidin-3 -y1)methyl)isoxazole-5 -carboxamide (R)-\ -((1-cyanopyrrolidin-3 thy1)- lH-benzo [d]imidazole-Z-carboxamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)isoquinoline-3 -carboxamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methy1)-5 -pheny1isoxazole-3 -carboxamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)pheny1picolinamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)-5 -pheny1picolinamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)-5 -pheny1thiazolecarboxamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)pheny1thiazolecarboxamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)pheny1-1H-pyrazole-3 -carboxamide (R)-\ -((1-cyanopyrrolidin-3 -y1)methyl)pheny1- dazole-S -carboxamide (R)chloro-N-((1-cyanopyrrolidin-3 -yl)methyl)imidazo[ 1 ,2—a]pyridinecarboxamide (R)-3 -(2-chloropheny1)-N-((1-cyanopyrrolidin-3 -y1)methyl)isoxazole-5 -carboxamide (R)-3 -(4-chlorophenyl)-N-(( l -cyanopyrrolidin-3 -yl)methyl)isoxazole-5 -carboxamide (R)-5 -(3 -cyanophenyl)-N-(( l pyrrolidin-3 -yl)methyl)- l ,3 ,4-oxadiazolecarboxamide (S)-5 -(3 -cyanophenyl)-N-(( l -cyanopyrrolidin-3 -yl)methyl)- l ,3 ,4-oxadiazolecarboxamide (R)-N-(( l -cyanopyrrolidin-3 -yl)methyl)- l -phenyl- lH-imidazolecarboxamide (R)- l -(3 -cyanophenyl)-N-(( l -cyanopyrrolidin-3 -yl)methyl)- lH-imidazolecarboxamide (R)- l -(4-cyanophenyl)-N-(( l -cyanopyrrolidin-3 -yl)methyl)- lH-imidazolecarboxamide (R)-N-(( l -cyanopyrrolidin-3 -yl)methyl)- l -(2-methoxyphenyl)- lH-imidazolecarboxamide (( l -cyanopyrrolidin-3 -yl)methyl)- l -(3 -methoxyphenyl)- lH-imidazolecarboxamide (R)-N-(( l pyrrolidin-3 -yl)methyl)( lH-pyrazolyl)imidazo[ l ,2—a]pyridinecarboxamide (R)-N-(( l -cyanopyrrolidin-3 thyl)( lH-pyrazol-3 -yl)imidazo[ l ,2—a]pyridinecarboxamide (R)-N-(( l pyrrolidin-3 -yl)methyl)cyclopropylimidazo[ l ,2—a]pyridinecarboxamide (R)- l l-N-(( l -cyanopyrrolidin-3 -yl)methyl)- lH-imidazolecarboxamide (R)-N-(( l -cyanopyrrolidin-3 -yl)methyl)- l -(cyclopropylmethyl)- lH-imidazolecarboxamide or pharmaceutically acceptable salts f.
It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.
According to a fithher aspect of the invention there is provided a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof comprising the steps of reacting an amine of formula (II) with a compound A-L-LG to form a compound of formula (III): (111) wherein R", Rlb, R", R", R15, R", ng, R2, A, X, L and m, are as defined elsewhere, PG is an amine protecting group and LG is a le leaving group. The protecting group may be but is not limited to BOC. It is clear to a person skilled in the art to combine or adjust such a protecting chemical group. The leaving group may be but is not limited to halogen. It is clear to a person d in the art to combine or adjust such a chemical leaving group. The protecting group may be removed to leave the free amine according to formula (IV) which can then be treated with cyanogen bromide to form compounds ing to formula (I): wherein R", Rlb, R", R", R15, R", ng, R2, A, X, L and m are as defined elsewhere.
According to a fithher aspect of the invention there is provided a process for the preparation of a nd of formula (I) or a pharmaceutically acceptable salt thereof comprising the steps of reacting an amine of formula (IV) with cyanogen bromide to form N-CN compounds: v 2:13 'w i} *R 1;: s s ‘ i i mm h x, . "x 3" \Nn" '\., ix-:, "I" ‘2‘ § "" a ix ,1 x : "g- . s ‘>.-\ 1 A x . . . s N H \ r s i S ' u '- \ X, 3" .- F)?" I"? RV '< § <5:\"-\"__» 2" Hex—"M i .‘ R8,}. 3 ‘ ES t i E: ii F": wherein R", Rlb, R", R", R15, R", ng, R2, A, X, L and m are as defined ere.
According to a fithher aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention.
Pharmaceutical itions of this invention comprise any of the compounds of the invention combined with any pharmaceutically acceptable carrier, nt or vehicle. Examples of pharmaceutically acceptable carriers, are known to those d in the art and include but are not limited to preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifiJngal agents, lubricating agents and dispersing agents, ing on the nature of the mode of administration and dosage forms. The compositions may be in the form of, for example, tablets, capsules, powders, granules, elixirs, lozenges, suppositories, syrups and liquid preparations including sions and solutions. The term "pharmaceutical composition" in the context of this invention means a ition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers. The composition may fithher 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, perfiJming agents, antibacterial agents, ngal agents, lubricating agents and dispersing agents, ing on the nature ofthe mode of administration and dosage forms.
The compounds of the invention can be used in the treatment of disorders and diseases related to USP30 inhibition.
Conditions Involving Mitochondrial Dysfunction The compounds of the invention can be used in the treatment of ers or diseases having a component ng to mitochondrial dysfiJnction, particularly disorders or es linked to DUB activity. More ularly, disorders or diseases link to USP30 activity.
The compounds described herein may be used in the cture of a medicament for the treatment of conditions involving mitochondrial dysfiinction.
In a fithher aspect of the invention there is provided a method of treatment or prevention of a condition ing mitochondrial ction, the method comprising administering a pharmaceutically effective amount of a nd of the ion or a pharmaceutical composition thereof to an individual diagnosed with a condition involving mitochondrial dysfiinction.
Mitochondrial dysfiJnctions result from defects of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When ondria fail, less and less energy is ted Within the cell and cell injury or even cell death will follow. If this process is repeated throughout the body the life of the subject in Whom this is happening is severely compromised. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.
The condition involving mitochondrial dysfiJnction may be selected from a condition involving a mitophagy defect, a condition ing a mutation in mitochondrial DNA, a ion involving ondrial oxidative stress, a condition involving a defect in mitochondrial membrane potential, mitochondrial biogenesis, a condition involving a defect in mitochondrial shape or morphology, and a condition involving a lysosomal storage defect.
In particular, the condition involving mitochondrial dysfiJnction may be selected from a neurodegenerative disease, multiple sclerosis (MS), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, Leber's hereditary optic neuropathy (LHON), cancer, neuropathy, ataxia, retinitis pigmentosa-maternally ted Leigh syndrome (NARP-MILS), Danon disease, diabetes, diabetic nephropathy, metabolic disorders, heart failure, ischemic heart disease leading to myocardial infarction, psychiatric diseases, for example schizophrenia, multiple sulfatase ency (MSD), mucolipidosis II (ML II), mucolipidosis III (ML III), mucolipidosis IV (ML IV), GMl-gangliosidosis (GMl), neuronal ceroid-lipofiJscinoses (NCLl), Alpers disease, Barth syndrome, Beta-oxidation s, ne-acyl-camitine deficiency, camitine deficiency, creatine deficiency syndromes, co-enzyme Q10 ency, complex I deficiency, x II ncy, complex III deficiency, complex IV deficiency, complex V deficiency, COX deficiency, chronic progressive external ophthalmoplegia syndrome (CPEO), CPT I deficiency, CPT II deficiency, glutaric aciduria type II, Keams-Sayre syndrome, lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency (LCHAD), Leigh disease or syndrome, lethal ile cardiomyopathy (LIC), Luft disease, glutaric aciduria type II, medium-chain oA dehydrogenase deficiency (MCAD), myoclonic epilepsy and ragged-red fiber (MERRF) syndrome; ondrial thy; mitochondrial recessive ataxia syndrome; mitochondrial DNA depletion syndrome; rogastointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium/short-chain 3-hydroxyacyl- CoA dehydrogenase (M/SCHAD) deficiency; and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency; and pendent decline in cognitive function and muscle strength.
The condition involving mitochondrial dysfiJnction may be a CNS disorder; for example a neurodegenerative disease.
Neurodegenerative diseases include; but are not limited to; Parkinson’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); gton’s disease; ischemia; stroke; dementia with Lewy bodies; and frontotemperal dementia.
In a particular embodiment; the compounds ofthe invention are useful in the treatment of Parkinson’s disease; ing; but not d to; PD related to mutations in a-synuclein; parkin and PINKl; mal recessive juvenile Parkinson’s disease (AR-JP) Where parkin is mutated.
The nds of the invention or pharmaceutical compositions thereof as described herein may be combined with one or more additional agents when used for the treatment of conditions involving mitochondrial ction. The compounds may be combined with one or more onal agents selected from levodopa; a dopamine t; a monoamino oxygenase (MAO) B inhibitor; a catechol O-methyltransferase (COMT) inhibitor; an anticholinergic; riluzole; amantadine; a cholinesterase inhibitor; memantine; tetrabenazine; an antipsychotic; diazepam; clonazepam; an antidepressant; and an anti-convulsant.
Cancer Compounds of the invention also have use in the ent of cancer and more particularly in the treatment of cancer linked to DUB activity; especially USP30 activity.
The nds as described herein may also be used in the manufacture of a medicament for the treatment of a cancer. In a further aspect of the invention there is provided a method of treatment or prevention of a cancer; the method comprising administering a ceutically effective amount of a compound of the invention or a pharmaceutical composition thereof to an individual suffering from a cancer.
The compounds of the invention also have use in the treatment of cancer linked to mitochondrial dysfiinction.
In one embodiment, the compounds of the invention have use in the treatment of cancer where tic pathways are dysregulated and more particularly where proteins of the BCL-2 family are mutated, or over or under sed.
References to "cancer" or "tumour" include but are not limited to breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, as, brain, melanoma, bone or other cancers of tissue organs and cancers of the blood cells such as mas and leukaemias. Particular cancers include lymphoma, multiple myeloma, colorectal cancer, and non-small cell lung carcinoma.
The compounds of the ion or pharmaceutical compositions thereof as described herein may be combined with one or more additional agents when used for the treatment of cancer. The compounds may be combined with an additional anti-tumour therapeutic agent, for example chemotherapeutic drugs or inhibitors of other regulatory proteins. In one embodiment the additional anti-tumour therapeutic agent is a BH-3 mimetic. In a fithher embodiment BH-3 mimetics may be selected from but not limited to one or more of ABT-737, ABT-l99, 3, and ObatoclaX. In a fithher embodiment the additional anti-tumour agent is a chemotherapeutic agent. Chemotherapeutic agents may be selected from but not limited to, olaparib, mitomycin C, cisplatin, latin, oxaliplatin, ng ion (IR), camptothecin, irinotecan, topotecan, temozolomide, taxanes, 5- fluoropyrimidines, gemcitabine, and doxorubicin.
Dosage Forms For treating a mitochondrial dysfiJnction disorder, the pharmaceutical compositions of the invention may be designed for stration by the oral, parenteral or mucosal route and the choice or the specific form of composition is ent on the administration route. Thus for oral administration the composition may be in the form, for example, of tablets, lozenges, dragees, films, powders, s, syrups, liquid preparations including dispersions, suspensions, emulsions, ons or sprays, cachets, granules, capsules, etc. For administration to mucosa the composition may be in the form of , inhalants, dispersions, suspensions, emulsions, solutions, gels, patches, films, ointments, creams, lotions, suppositories etc. For parenteral administration the composition is in the form of a liquid preparation such as a solution, dispersion, emulsion or suspension including liposome compositions.
For treating a CNS disorder, the nds of the invention must have the ability to pass across the blood-brain barrier. As such, such compounds have the ability to enter the central s system of a patient. Alternatively, the ceutical compositions of the present invention can bypass the blood brain barrier h use of compositions and methods known in the art for bypassing the blood brain barrier or can be injected directly into the brain. Suitable areas for inj ection include the cerebral cortex, cerebellum, midbrain, brainstem, hypothalamus, spinal cord and ventricular tissue, and areas of the PNS including the carotid body and the l medulla. Further dosage forms include those suitable for oral delivery including, but not limited to tablets, s, powders, eliXirs, syrups, liquid preparations including sions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules and capsules. For parenteral administration, preparations include sterile aqueous, aqueous- organic, and organic solutions, suspensions and emulsions.
For treating a cancer, the pharmaceutical compositions of the invention may be administered in any effective manner suitable for targeting cancer cells, for e orally in any orally acceptable dosage form including, but not limited to tablets, dragees, powders, eliXirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules and capsules. Preparations according to the invention for parenteral stration include sterile s, s-organic, and organic solutions, suspensions and emulsions.
Such dosage forms are prepared according to techniques known in the art of pharmaceutical formulation. When in the form of sprays or inhalants the pharmaceutical itions may be administered nasally. Suitable formulations for this purpose are known to those skilled in the art.
The pharmaceutical compositions of the invention may be administered by injection and may be in the form of a sterile liquid preparation for injection, including liposome preparations. The pharmaceutical compositions of the invention may also be in the form of suppositories for rectal administration.
These are formulated so that the pharmaceutical ition is solid at room ature and liquid at body temperature to allow release of the active compound.
The dosages may be varied depending upon the requirements of the patient, the ty of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the remit of the person skilled in the skill of the art. Generally, treatment is ted with smaller dosages which are less than the optimal dose of the compound. Thereafter the dosage is increased by small ents until the optimum effect under the circumstances is reached.
The magnitude of an ive 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, t undue burden. The daily dose range is about lOug to about 100 mg per kg body weight of a human and non- human animal and in general may be around 10ug to 30mg per kg body weight per dose. The above dose may be given from one to three times per day.
Synthetic methodologies Compounds of the invention may be prepared via a variety of synthetic routes. Exemplary routes to certain nds of the invention are shown below. Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the s are an illustration, the invention should not be construed as being limited by the al reactions and conditions expressed. The ation of the various starting als used in the schemes is well within the skill of persons versed in the art. Those skilled in the art appreciate that, where appropriate, the individual ormations within a scheme can be completed in a different order. The following schemes describe general synthetic methods whereby intermediate and target compounds of the present invention may be prepared. Additional representative compounds and stereoisomers, racemic mixtures, diastereomers and enantiomers thereof can be synthesized using the ediates prepared in accordance to the general schemes and other materials, compounds and reagents known to those skilled in the art. All such compounds, stereoisomers, racemic mixtures, diastereomers and enantiomers thereof are intended to be encompassed within the scope of the present invention.
All the compounds were characterised by liquid chromatography-mass spectroscopy (LCMS) and 1H Abbreviations: BINAP 2,2'-Bis(diphenylphosphino)- l , l'-binaphthyl Boc Tert-butoxycarbonyl br Broad (NMR ) CD1 1, l-Carbonyldiimidazole d Doublet (NMR signal) dba dibenzylideneacetone DBU l,8-Diazabicyclo[5.4.0]undecene DCM Dichloromethane DIPEA Diisopropylethylamine DMA Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethylsulphoxide dppf l, l'-Bis(diphenylphosphino)ferrocene ES Electrospray EtOAc Ethyl acetate EtOH Ethanol h Hour(s) Hal n, e.g. F, Cl, Br, I HATU l-[Bis(dimethylamino)methylene]-lH-1,2,3 -triazolo [4,5 -b]pyridinium3 -oxid hexafluorophosphate m Multiplet (NMR signal) MeCN Acetonitrile Me-Dalphos Di( 1 ntyl)dimethylaminophenylphosphine MeOH Methanol MTBE Methyl teIt-butyl ether NMP N—methyl-2—pyrrolidone PE Petroleum ether rt Room ature Ruphos 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl s Singlet (NMR signal) t Triplet (NMR signal) T3P Propylphosphonic anhydride TBD 1,5,7-triazabicyclo[4.4.0]dec-5 -ene TEA Triethylamine TFA Trifluoroacetic acid THF TetrahydrofiJran TLC Thin Layer Chromatography TMA Trimethylaluminium LCMS Methods Method A Column X-bridge C18, 50 X4.6mm, 3 .5um or equivalent (A) 0.1% Ammonia in water Mobile Phase (B) 0.1% Ammonia in MeCN Flow Rate 1.0 mL/min Gradient Time %B 0.0 l 5 .00 90 .80 95 7.20 95 7.2 l 5 .00 5 Method B Column BEH C18, 50 X2. 1mm, 1.7um or equivalent (A) 5mM Ammonium acetate + 0.1% formic acid in water Mobile Phase (B) 0.1% Formic acid in MeCN Flow Rate 0.45 mL/min Gradient Time %B 0.01 2 0.50 2 .00 90 6.00 95 7.00 95 7.01 2 8.00 2 Method C Column BEH C18, 50 X2. 1mm, 1.7um or equivalent (A) 5mM Ammonium acetate + 0.1% formic acid in water Mobile Phase (B) 0.1% Formic acid in MeCN Flow Rate 0.55 mL/min Gradient Time %B 0.01 5 0.40 5 0.80 35 1.20 55 2.50 100 3.30 100 3.31 5 4.00 5 Method D Colunm Agilent , 50 X2.1mm, 5um (A) 0.04% TFA in water Mobile Phase (B) 0.02% TFA in MeCN Flow Rate 0.8 mL/min Gradient Time %B 0 0 0.4 0 3.4 100 4 100 Temperature 40°C Method E Column Agilent TC-C18, 50 X2. 1mm, 5pm (A) 0.04% TFA in water Mobile Phase (B) 0.02% TFA in MeCN Flow Rate 0.8 mL/min Gradient Time %B 0 0 0.4 1 3 .4 100 4 100 Temperature 50°C Method F Colunm e ShieldRPlS, 2.1 X50mm, 5um (A) 0.05% Ammonia in water Mobile Phase (B) MeCN Flow Rate 0.8 mL/min Gradient Time %B 0 0 0.4 5 3 .4 100 4 100 Temperature 40°C Method G Column X-bridge C18, 250 X4.6mm, 5um or equivalent (A) 0.1% Ammonia in water Mobile Phase (B) 0.1% Ammonia in MeCN Flow Rate 1.0 mL/min Gradient Time %B 0.01 5 .00 5 .00 30 .00 30 .00 60 .00 90 .00 90 .01 5 40.00 5 Example 1 3-((Quinolin-Z—ylamin0)methyUpyrrolidine-I-carb0nitrile oir a CCla / b / e / Him—<0 0 a CCl 2 Cfil N HEN—«f N no N Mme Step a. To a solution of tert-butyl 3-(aminomethyl)pyrrolidinecarboxy1ate (0.2 mmol), 2- chloroquinoline (0.2 mmol) and sodium tert-butoxide (0.6 mmol) in toluene (1 ml) were added catalytic amounts of allyl palladium and Me-Dalphos at rt under en. The reaction mixture was stirred at 65°C for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting e was purified by prep-TLC OAc 1:1) yielding tert-butyl 3-((quinolin ylamino)methy1)-pyrrolidinecarboxylate. MS: ES+ 328.4.
Step b. To a on of tert-butyl tert-butyl 3-((quinoliny1amino)methy1)pyrrolidinecarboxy1ate in EtOAc (1 mL) was added 4 M HCl in EtOAc (1 ml). The reaction mixture was stirred at rt for 2 h.
The resulting mixture was concentrated under d pressure. The residue N-(pyrrolidin ylmethy1)-quinolinamine was used directly in the next step without fithher purification. MS: ES+ 228.1.
Step c. To a solution of N-(pyrrolidiny1methy1)quinolinamine in EtOH (2 mL) was added cyanogen bromide (0.2 mmol) and NaHC03 (0.6 mmol). The reaction mixture was d at rt for 16 h. The resulting mixture was trated under reduced pressure. The crude was purified by preparative reverse phase HPLC (A: 0.078% ammonium acetate in water, B: MeCN) yielding the title compound (1.5 mg, 0.005 mmol). LCMS: Method E, retention time 1.98 min, MS: ES+ 254.1.
Compounds in Table 1 were synthesised using a procedure similar to that described for Example 1.
R. 4. N .5—N Hal HACN Table 1 LCMS LCMS RT MS EX R Name Method (min) ES+ LCMS LCMS RT MS Ex Name Method (min) ES+ 3-(((6—Flu0r0benzo[d]thiazol—2- yl)amino)methpryrrolidine-I- 2.18 277.1 carbonitrile 3-((Is0quinolin ylamino)methpryrrolidine-I - 1.775 253.1 carbonitrile 3-(((3-Phenylpyridin no)methpryrrolidine-I- 1.915 279.2 carbonitrile -Phenylpyridin yl)amino)methpryrrolidine-I- 2.239 279.0 carbonitrile 3-(((5-Phenylpyridin yl)amino)methpryrrolidine-I- 2.225 279.0 carbonitrile 3-(((6—Phenylpyridin yl)amino)methpryrrolidine-I- 2.16 279.0 carbonitrile 3-(((4-Phenylpyrimidin no)methpryrrolidine-I- 2.35 280.0 carbonitrile Example 9 (R)(((5-Phenylthiazolyl)amino)methyl)pyrrolidinecarb0nitrile S*1inI 4» SABrl 4» N/’I. W1?°" -EN Step a. To a solution of 5-pheny1thiazolamine (10.0 g, 56.8 mmol) in MeCN (200 ml) was added CuBrz (15.2 g, 68.18 mmol) at 0°C and stirred for 10 min. Tert-butyl nitrite (8.10 ml, 68.2 mmol) was added drop wise to the reaction mixture at 0°C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture filtered through celite hyflow. The celite cake was washed with MeCN (2 X 100 ml). The filtrate was concentrated under reduced re and diluted with water (100 ml). The resulting mixture was extracted with EtOAc (3 X 80 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The ing residue was purified by column chromatography (30% EtOAc in ) yielding 2-bromo-5 -phenylthiazole (2.00 g, 8.33 mmol). LCMS: Method B, 4.78 min, MS: ES+ 24020, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.13 (s, 1 H), 7.65 - 7.67 (m, 2 H), 7.45 - 7.49 (m, 2 H), 7.39 - 7.43 (m, 1 H).
Step b. To a solution of 2-bromophenylthiazole (0.30 g, 1.24 mmol) in EtOH (5 ml) was added tert-butyl (R)(aminomethyl)pyrrolidinecarboxylate (0.274 g, 1.36 mmol) at It. The reaction mixture was heated at 100°C for 120 h. The resulting reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by column chromatography (40% EtOAc in hexane) yielding tert-butyl (R)(((5 -phenylthiazolyl)amino) methyl)pyrrolidine- l-carboxylate (0.12 g, 0.33 mmol). LCMS: Method B, 4.27 min, MS: ES+ .
Step c. To a solution of tert-butyl (R)(((5-phenylthiazolyl)amino)methyl)pyrrolidine carboxylate (0.11 g, 0.30 mmol) in DCM (8 ml) was added TFA (0.5 ml) at 0°C. The reaction mixture was stirred at rt for 1 h. The resulting reaction mixture was concentrated under reduced re. The obtained residue was redistilled using DCM (2 x 5 ml). The obtained residue was triturated with diethyl ether (2 x 5 ml) yielding (R)phenyl-N-(pyrrolidinylmethyl)thiazolamine TFA salt (0.095 g, 0.25 mmol). This material was ly used for the next step without fithher purification.
Step (1. To a solution of (R)phenyl-N-(pyrrolidinylmethyl)thiazolamine TFA salt (0.09 g, 0.34 mmol) in THF (10 ml) was added K2C03 (0.143 g, 1.00 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 min. Cyanogen bromide (0.044 g, 0.41 mmol) was added to the reaction e at 0°C. The reaction mixture was stirred at rt for 30 min. The resulting on e was poured into water (20 ml) and extracted with EtOAc (2 x 25 ml). The combined c phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was d by column chromatography (70% EtOAc in hexane) yielding title compound (0.038 g, 0.13 mmol). LCMS: Method B, 3.37 min, MS: ES+ 28533, 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.94 (m, 1H), 7.33 - 7.49 (m, 5 H), 7.16 - 7.22 (m, 1 H), 3.39 - 3.51 (m, 2 H), 3.27 - 3.36 (m, 3 H), 3.12 - 3.18 (m, 1 H), 2.53 - 2.59 (m, 1 H), 1.94 - 2.04 (m, 1 H), 1.64 - 1.72 (m, 1 H).
Example 10 (S)(((5-Phenylthiazol-Z—yl)amin0)methyl)pyrrolidine-I-carb0nitrile Mk"/N flu-EN The title compound was synthesised by a procedure similar to Example 9 using tert-butyl (S) (aminomethyl)pyrrolidinecarboxylate. LCMS: Method B, 3.40 min, MS: ES+ 28568, 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.94 (br t, J=5.2 Hz, 1 H), 7.47 (s, 1 H), 7.42 - 7.44 (m, 2 H), 7.32 - 7.35 (m, 2 H), 7.17 - 7.21 (m, 1 H), 3.42 - 3.49 (m, 2 H), 3.34 - 3.39 (m, 1 H), 3.26 - 3.29 (m, 2 H), 3.13 - 3.17 (m, 1 H), 2.53 - 2.59 (m, 1 H), 1.95 —2.03 (m, 1 H), 1.62 - 1.71 (m, 1H).
Example 11 3-(((6—(1H—Pyrazolyl)benzo[d]thiazol-2—yl)amin0)methyl)pyrrolidinecarb0nitrile Step a. To a solution of 6-bromochloro-1,3-benzothiazole (0.1 g, 0.40 mmol) and tert-butyl 3- (aminomethyl)pyrrolidinecarboxy1ate (0.08 g, 0.40 mmol) in THF (2.5 ml) was added TEA (0.11 ml, 0.80 mmol) at rt. The reaction mixture was heated at 90°C for 16 h, before cooling to rt and concentrating under reduced pressure. The residue was purified by column chromatography % EtOAc in hexane) yielding tert-butyl 3-(((6-bromobenzo[d]thiazoly1)amino)methy1)pyrrolidine carboxylate (0.105 g, 0.25 mmol). LCMS: Method C, 2.66 min, MS: ES+ 412.30.
Step b. A solution of tert-butyl 3-(((6-bromobenzo[d]thiazoly1)amino)methy1)pyrrolidine carboxylate (0.25 g, 0.60 mmol) and 4-(4,4,5,5-tetramethy1—1,3,2-dioxaborolanyl)-1H-pyrazole (0.12 g, 0.60 mmol) in er (9:1, 5 ml) was prepared in a microwaveable glass Vial and treated with NaHC03 (0.105 g, 1.21 mmol). The reaction mixture was degassed for 10 min at rt before addition of Pd(dppf)C12 (0.022 g, 0.03 mmol). The on mixture was subjected to microwave heating at 140°C for 1.5 h. The resulting mixture was poured into water (100 m1) and extracted with EtOAc (3 X 30 ml). The combined organic phase was washed with brine solution (2 X 25 m1), dried over NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (7-8% MeOH in DCM) yielding tert-butyl 3-(((6-(1H-pyrazoly1)benzo[d]thiazol- 2-y1)amino)-methy1)pyrrolidinecarboxy1ate (0.12 g, 0.30 mmol). LCMS: Method C, 1.98 min, MS: ES+ .
Step c. To a on of tert-butyl 3-(((6-(1H-pyrazoly1)benzo[d]thiazoly1)amino)methy1) pyrrolidine-l-carboxylate (0.12 g, 0.30 mmol) in DCM (3 ml) was added TFA (1.2 ml) at 0°C. The reaction e was stirred at rt for 1 h. The resulting reaction e was concentrated under reduced pressure ng 6-(1H-pyrazoly1)-N-(pyrrolidiny1methy1)benzo[d]thiazolamine TFA salt (0.10 g, 0.24 mmol). This material was directly used for the next step without filI'tl’lCl‘ purification. LCMS: Method C, 1.37 min, MS: ES+ 300.39.
Step d. To a solution of 6-(1H-pyrazolyl)-N-(pyrrolidinylmethyl)benzo[d]thiazolamine TFA salt (0.10 g, 0.24 mmol) in DMF (2.5 ml) was added K2C03 (0.085 g, 0.60 mmol) at 0°C. Cyanogen bromide (0.03 g, 0.29 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 10°C for 45 min. The resulting on mixture was poured into ice cold water (40 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phase was washed with brine solution (20 ml), dried over NaZSO4, d and concentrated under reduced pressure. The resulting residue was purified by column chromatography (3 -6% MeOH in DCM) yielding the title compound (0.03 g, 0.09 mmol). LCMS: Method A, 3.21 min, MS: ES+ 32496, 1H NMR (400 MHz, DMSO-d6) 5 ppm 12.86 (s, 1 H), 8.11 - 8.13 (m, 2 H), 7.88 - 7.92 (m, 2 H), 7.47 (dd, , 1.60 Hz, 1 H), 7.35 (d, J=8.40 Hz, 1 H), 3.43 - 3.51 (m, 2 H), 3.33 - 3.40 (m, 3 H), 3.15 - 3.19 (m, 1 H), 2.55 - 2.62 (m, 1 H), 1.98 - 2.03 (m, 1 H), 1.67 - 1.72 (m, 1 H).
Example 12 (R)(((7—(1H—Pyrazolyl)quinazolin-Z—yl)amin0)methyl)pyrrolidinecarb0nitrile QC) i £61 N L K1 L JCQ,, \ \ Br N N 0+ Br F Br N NH2 Br N | H CN‘< HN‘: :NXHIH/"CN;N <— HNC/j/CIJXHM"ON-"40% N N Step a. To a solution of 2-fluorobromobenzaldehyde (5.0 g, 24.63 mmol) in DMA (50 ml) was added guanidine carbonate (6.65 g, 36.94 mmol) at rt. The reaction mixture was heated at 140°C for 2 h. The resulting reaction mixture was poured into ice cold water (500 ml). The resultant white precipitate was collected by filtration and then suspended in 2 M HCl (150 ml). The sion was stirred well to obtain a hazy suspension, before filtering to remove un-dissolved solids. The clear filtrate was collected and washed with diethyl ether (3 x 50 ml). The obtained aqueous layer was basified using 2 M NaOH solution (100 ml). The ed white precipitates were collected by filtration, washed with e (3 x 10 ml) and dried under vacuum yielding 7-bromoquinazolin amine (0.80 g, 3.57 mmol). LCMS: Method C, 1.62 min, MS: ES+ 224.11, 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.13 (s, 1 H), 7.75 (d, J=8.4 Hz, 1 H), 7.59 (d, J=2.0 Hz, 1 H), 7.36 (dd, J=8.4, 2.0 Hz, 1 H), 7.08 (s, 2 H).
Step b. To a solution of oquinazolinamine (0.80 g, 3.57 mmol) in THF (15 ml) was added CuI (0.34 g, 1.70 mmol) and CH212 (0.94 g, 3.50 mmol) at It. Isoamyl nitrite (1.44 ml, 10.50 mmol) was added drop wise to the reaction mixture at rt. The reaction mixture was heated at 80°C for 4 h.
The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (3 x 30 ml).
The combined organic phase was collected, d through celite hyflow. The obtained filtrate was dried over Na2SO4, d and concentrated under reduced pressure. The resulting residue was purified by column chromatography (15% EtOAc in ) yielding 7-bromoiodoquinazoline (0.34 g, 1.01 mmol). LCMS: Method C, 2.25 min, MS: ES+ 33520, 1H NMR (400 MHz, DMSO-d6) ppm 9.38 (s, 1 H), 8.24 (d, J=2 Hz, 1 H), 8.13 (d, J=8.8 Hz, 1 H), 7.96 (dd, J=8.8, 2 Hz, 1 H).
Step c. A solution of 7-bromoiodoquinazoline (0.33 g, 0.98 mmol) and tert-butyl (R) (aminomethyl) pyrrolidinecarboxylate (0.198 g, 0.98 mmol) in NMP (10 ml) was prepared in a microwaveable glass vial. DIPEA (0.34 ml, 1.96 mmol) was added to the reaction mixture at rt. The glass vial was sealed and ted to microwave irradiation at 70°C for 30 min. The ing on mixture was poured into brine solution (100 ml) and ted with EtOAc (3 x 20 ml). The ed organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced re. The resulting residue was purified by column chromatography (30% EtOAc in hexane) yielding tert-butyl (R)(((7-bromoquinazolinyl)amino)methyl)pyrrolidinecarboxylate (0.80 g, quantitative). LCMS: Method C, 2.59 min, MS: ES+ 407.50.
Step (1. A solution of tert-butyl (R)(((7-bromoquinazolinyl)amino)methyl)pyrrolidine carboxylate (0.75 g, 1.84 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.39 g, 2.00 mmol) in DMszater (4:1, 10 ml) was prepared in a microwaveable glass vial. NaHC03 (0.30 g, 3.60 mmol) was added to the reaction mixture at It. The mixture was degassed for 10 min at rt before addition of Pd(dppf)C12 (0.065 g, 0.09 mmol). The reaction mixture was subjected to microwave heating at 150°C for 30 min. The resulting reaction mixture was poured into brine solution (100 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was d by column chromatography (4% MeOH in DCM) yielding tert-butyl (R)(((7-(1H-pyrazolyl)quinazolin no)methyl)pyrrolidinecarboxylate (0.205 g, 0.52 mmol). LCMS: Method C, 1.80 min, MS: ES+ 39565, 1H NMR (400 MHz, DMSO-d6) 5 ppm 13.10 (s, 1 H), 9.00 (s, 1 H), 8.44 (s, 1 H), 8.12 (s, 1 H), 7.75 (d, J=8.40 Hz, 1 H), 7.70 (s, 1 H), 7.53 (dd, J=8.40, 1.60 Hz, 2 H), 3.34 - 3.39 (m, 3 H), 3.16 - 3.24 (m, 1 H), 3.03 - 3.07 (m, 1 H), 2.51 - 2.62 (m, 2 H), 1.94 - 1.97 (m, 1 H), 1.61 - 1.66 (m, 1 H), 1.39 (s, 9 H).
Steps e, f. The title compound was synthesised following the procedure in Example 9, steps c, d.
LCMS: Method A, 3.23 min, MS: ES+ 32004, 1H NMR (400 MHz, DMSO-d6) 5 ppm 13.10 (s, 1 H), 9.09 (s, 1 H), 8.44 (s, 1 H), 8.12 (s, 1 H), 7.76 (d, J=8.40 Hz, 1 H), 7.70 (s, 1 H), 7.54 (dd, J=8.00, 1.20 Hz, 2 H), 3.44 - 3.50 (m, 2 H), 3.36 - 3.40 (m, 3 H), 3.20 - 3.24 (m, 1 H), 2.61 - 2.67 (m, 1 H), 1.95 - 2.02 (m, 1 H), 1.70 - 1.76 (m, 1 H).
Example 13 Terr-bulyl 3-(((3-(1,3-dimethyl-IH-pyrazolyl) phenyl) amino) methyl) pyrrolidine carboxylate Step a. To a solution of 1-bromonitrobenzene (0.25 g, 1.23 mmol) and 1,3-dimethyl(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.33 g, 1.48 mmol) in DMszater (1: 1, 4 ml) was added NaHC03 (0.319 g, 3.70 mmol) at It. The mixture was degassed for 15 min before addition of PdC12(dppf) (0.09 g, 0.12 mmol). The reaction mixture was heated at 100°C for 2 h. The resulting mixture was poured into water (150 ml) and extracted with EtOAc (3 x 100 ml). The organic phase was collected, dried over , filtered and trated under reduced pressure to yielding 1,3- dimethyl(3-nitrophenyl)-1H-pyrazole (0.28 g, 1.28 mmol). LCMS: Method C, 2.12 min, MS: ES+ 218.53. The crude material was used for next step without ation.
Step b. To a solution of 1,3-dimethyl(3-nitrophenyl)-1H-pyrazole (0.28 g, 1.28 mmol) in methanolzTHF (1 : 1, 6 ml) was added 20% Pd(OH)2 (50% moisture, 0.3 g) at rt. The reaction mixture was purged with H2 gas at rt for 2 h. The resulting reaction mixture was carefiilly filtered h celite hyflow and concentrated under reduced pressure to yielding 3-(1,3-dimethyl-1H-pyrazol yl)aniline (0.2 g, 1.06 mmol). LCMS: Method C, 1.52 min, MS: ES+ 188.39. The crude material was used for next step without purification.
Step c. To a solution of 3-(1,3-dimethyl-1H-pyrazolyl)aniline (0.2 g, 1.06 mmol) and tert-butyl 3- formylpyrrolidinecarboxylate (0.27 g, 1.39 mmol) in DCM (5 ml) was added TEA (0.13 g, 1.28 mmol) at rt. The reaction mixture was stirred at 70°C for 16 hrs. Sodium toxyborohydride (0.45 g, 2.12 mmol) was added to the reaction mixture at 0°C and stirred at rt for 16 h. The resulting reaction mixture was poured into water (100 ml) and ted with DCM (3 x 100 ml). The combined organic layer was washed with saturated solution of NaHC03 (100 ml), dried over NaZSO4, filtered and concentrated under reduced pressure to yielding tert-butyl 3-(((3-(1,3-dimethyl-1H- lyl)phenyl)amino)methyl)pyrrolidinecarboxylate (0.3 g, 0.8 mmol). LCMS: Method C, 2.38 min, MS: ES+ 371.53 Steps (1, e. The title compound was sised following the procedure in Example 9, steps c, d.
LCMS: Method B, 3.65 min, MS: ES+ 29638, 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.77 (s, 1 H), 7.06 (t, J = 7.6 Hz, 1 H), 6.57 - 6.60 (m, 2 H), 6.44 (dd, J = 1.6, 8.4 Hz, 1 H), 5.76 (t, J = 11.2 Hz, 1 H), 3.76 (s, 3 H), 3.34 - 3.52 (m, 4 H), 3.13 - 3.17 (m, 1 H), 3.03 (t, J = 12.8 Hz, 2 H), 2.26 (s,3 H), 1.99 - 2.04 (m, 1 H), 1.65 - 1.70 (m, 1 H). mH>H H+mmv $.03 ONHHN HKN 3.on mH>HoH .as: m: me am oH.m mH>HoH H262 m m < < "N: H - - - 63 Hflme "H5 6 SH H "H5 w "H5 mmN "HHH "HHH "HHH oNN "H5 "NHH mmN E u H "H5 H H H 3N Ho.» 3m HES SHAHHH"NHwauHJEEAHHH"NHHEwdHu "HHH "HHH "HHH N2 H 6 - é owm - - "N: H "N: HEAHH ONH "H5 N H mmN E w "HHH H - H mmN H - How 3% "H5 o H omm "H m: HV m3 Na 3H "N: OEWH "HE "HE 531 - HmN "HHH m 8an "HHH 3% - u "HHH "HHH "NHH N.m HoN m .3 H "EH "HHH Ha 3H N é53qu 3m - N - "HHH EH m $.H oafiaxm "H5 $8.1: 3H 8.» 2.1: H "N: - "NHH "a " "a N "a 3.1: "N "HHH w 8.» "H5 $.H u 3% Hm.» 30 m2 H u HN.N HHH "HHH H E HHH H - m H "EH "HHH all H N ON.m "H: "EH -:NAHHNéVomméNNHHHH "N:211 "H5 00$ é H H "HHH 63 N: "a "5;; "a "H5 - H é How é H . "H5 N . "HHH "HE HN.N "N: "H5 "N: HwN 8N conuomoc HHH>Hz HHN H "N: 8.» "HHH w; me o; H: "oomuH - "H: "me 3m o m - "HHH HHH 3.1: - "HHH - 8N u "HHH "3 "HHH OEWH "HHH - H OEWH E mam H N - d H H NoH H H H H "a mmm a é RN "H5 "H5 é é m: "H5 8H é é NHG "H5 "HHH ES H $5 "HHH N "HHH Now "HHHH EH "HHH "EH SN EH 8N mm.» "HHH H omm "HHH H3 mm.» "HHH "53:-ommAmN HN.N "HE 3:85 N 0:68on HHH 6.268: m a 08m Hg mam: z HHH -mHHHEHo: OmHHoMHHHaHHH .3 @352?me -EONSHHHHHH-HHHHHoeHnHfiHViVI -H-OHHHHHHHOHHHHHHHHHHHOEHOHHEHNHHHSHHHHHHH -Wm":meMHHHHHmHWHoHHWHMHHHWHHHHHMHHWHHWOWWHH 255833 . . 8% 258830 .
H 0-9; HHHOEHH H m cameo?" m-2H:88¢cmHHHHHHoHHHHHH-HH/H%MHHHMHMHHHHH6WHHHHHHH ouaaxoemoé , -- N - -, - , zH 283k L 7..
HHH Iz \ 12. \ o mcHHsomEoO _z\ z\ Oz 2 NIZ x .m 28g m E 2 S NH Example 18 ulyl 3-(((3-(1,3-dimethyl-IH-pyrazolyl) phenyl) amino) methyl) pyrrolidine ylate N / N / | —» N \ NH2 —» N N H NéN CI NH2 Step a. To a solution of 2-chloropyridinamine (0.5 g, 3.90 mmol) in toluene (12 ml) were added isoindoline hydrochloride (0.91 g, 5.85 mmol), BINAP (0.24 g, 0.39 mmol) and potassium tert- butoxide (2.07 g, 9.76 mmol) at It. The e was degassed for 10 min before addition of Pd2(dba)3 (0.178 g, 0.19 mmol). The reaction mixture was at 110°C for 4 hrs. The resulting mixture was poured into cold water (200 m1) and combined with two other batches prepared by an identical method on the same scale. The resulting mixture was extracted with DCM (3 X 100 ml). The organic phase was ted, dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (3% MeOH in DCM) ng 2-(isoindoliny1)pyridin amine (1.2 g, 5.67 mmol). LCMS: Method C, 1.57 min, MS: ES+ 212.29.
Steps b-d. The title nd was sised following the procedure in Example 12, steps c-e.
LCMS: Method A, 4.22 min, MS: ES+ 32010, 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.67 (d, J = 6 Hz, 1 H), 7.38 - 7.40 (m, 2 H), 7.29 - 7.32 (m, 2 H), 6.37 (t, J = 5.2 Hz, 1 H), 5.98 (dd, J = 1.6, 5.6 Hz, 1 H), 5.62 (d, J = 1.6 Hz, 1 H), 4.66 (s, 4 H), 3.44 - 3.52 (m, 2 H), 3.34 - 3.40 (m, 2 H), 3.08 - 3.16 (m, 3 H), 1.98 - 2.06 (m, 1 H), 1.65 - 1.70 (m, 1 H).
Example 19 (S)-3 -(((4-Pheny1pyrimidiny1)amino)methyl)pyrrolidinecarbonitrile / N / N fj:/ a b-d ’ \NJ\C| 4’ \NkNHEN —_‘N CI N CI Step a. A solution of chloropyrimidine (1.00g, 6.71 mmol), phenylboronic acid (0.90g, 7.38 mmol) in 1,4-dioxanezwater (8:2, 15 ml) was stirred at It. The reaction mixture was degassed for 15 min before addition of Cs2C03 (6.56 g, 20.13 mmol) and Pd(PPh3)4 (0.39g, 0.335 mmol). The reaction mixture was heated at 110°C for 14 h. The resulting reaction mixture was cooled to rt and poured into saturated NaHC03 solution (40 ml). The obtained mixture was extracted with EtOAc (2 x 25 ml). The combined organic phase was washed with brine solution (20 m1), dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (8% EtOAc in hexane) yielding rophenylpyrimidine (0.45g, 2.37 mmol). LCMS: Method C, 2.23 min, MS: ES+ 19157, 1H NMR (400 MHz, CDC13) 5 ppm 8.67 (d, J=5.2 Hz, 1 H), 8.11 - 8.13 (m, 2 H), 7.68 (d, J=5.6 Hz, 1 H), 7.54 - 7.58 (m, 3 H).
Steps b-d. The title compound was synthesised following the procedure in Example 9, steps b-d, using tert-butyl (S)(aminomethyl)pyrrolidinecarboxylate. LCMS: Method A, 4.20 min, MS: ES+ 28013, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.35 - 8.36 (m, 1 H), 8.02 - 8.17 (m, 2 H), 7.40 - 7.54 (m, 3 H), 7.15 - 7.16 (d, J=4.8 Hz, 1 H), 3.30 -3.49 (m, 6 H), 3.18 - 3.21 (m, 1 H), 1.95 - 2.00 (m, 1 H), 1.68 - 1.72 (m, 1 H).
Example 20 N-((1-Cyanopyrrolidin-3 -yl)methyl)phenyloxazole-5 -carboxamide O 0 O @4534 a mfiurigt a mommaa be Step a. To a on of 2-phenyloxazolecarboxylic (0.20 g, 1.06 mmol) in THF (5 ml) was added DIPEA (0.41 g, 3.17 mmol) and T3P (50% in EtOAc, 1.00 g, 1.58 mmol) at rt and stirred for 30 min.
The reaction mixture was treated with tert-butyl 3-(aminomethyl)pyrrolidinecarboxylate (0.26 g, 1.32 mmol) and stirred at rt for 3 h. The resulting reaction mixture was poured into saturated NaHC03 solution (20 ml) and extracted with EtOAc (2 x 10 ml). The combined organic phase was ted and washed with 10% citric acid solution (5 ml), dried over NaZSO4, filtered and trated under reduced pressure yielding tert-butyl 3-((2-phenyloxazole-5 -carboxamido)methyl)pyrrolidine carboxylate (0.25 g, 0.67 mmol). LCMS: Method C, 2.14 min, MS: ES+ 372.33.
Step b, c. The title nd was synthesised following the procedure in e 9, steps c, d and d by flash chromatography (60% EtOAc in hexane) yielding the title compound (0.050 g, 0.168 mmol). LCMS: Method B, 3.33 min, MS: ES+ 297.18, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.86 (t, J=5.6 Hz, 1 H), 8.12 - 8.14 (m, 2 H), 7.87 (d J=0.8 Hz, 1 H), 7.58 -7.61 (m, 3 H), 3.25 - 3.48 (m, 6 H), 3.16 - 3.20 (m, 2 H), 1.91 - 2.01 (m, 1 H), 1.66 - 1.73 (m, 1 H).
Compounds in Table 3.1 were synthesised using a procedure similar to that described for Example RJLOH JL R HEN—EN Table 3.1 LCMS LCMS RT MS EX R Name Method (min) ES+ %-— N—((I-C anoy pyrrolidin 21 E 2.59 297.1 N—o yl)methyl)phenylis0xazole LCMS LCMS RT MS EX R Name Method (min) ES+ carboxamide N—((1-Cyan0pyrrolidin 22 / —- yl)methyl)phenyl-1H—pyrazole- E 2.29 296.2 3-carb0xamide N—((1-Cyan0pyrrolidin OT" , yDmeth l)methy yl0x0-3,4- 23 F 1.91 315.2 0-2H-benzo[b][1, 4]0xazine- 6-carb0xamide N’l N—((1-Cyan0pyrrolidin 24 meethyD(pyridin F 2.14 307.1 yDbenzamide N—((1-Cyan0pyrrolidin m, yl)methyl)(0-tolyl)-1H-pyrazole- D 3 .27 310.2 N_NH 5-carb0xamide N—((1-Cyan0pyrrolidin 26 ©\(/i/7_—— yl)methyl)phenylthiazole D 3.52 313.1 carboxamide O Cyan0pyrrolidin 27 D 2.54 300.3 / \ __ meethyD(pyrrolidin /N pricolinamide Q0 N—((1-Cyan0pyrrolidin 28 meethyD-I-(Z4-dichlor0benzyl)- E 2.83 428.1 (EL/(NN\ 1H—indazolecarboxamide Q yl-N—((1-cyan0pyrrolidin 29 meethyD-IH—indazole E 2.52 360.2 (EL/(NN carboxamide N—((1-Cyan0pyrrolidin ‘ meethyDflv- D 3.30 385.2 phenylsulfamoyl)benzamide LCMS LCMS RT MS EX R Name Method (min) ES+ F N—((1-Cyan0pyrrolidin 31 %, yl)methyl)(2-flu0r0phenyl)-1H— E 2.37 314.0 N-NH pyrazolecarboxamide —— (E)-N—((1-Cyan0pyrr01idin \O,Q/f/ 32 meethyD(2-flu0r0 E 2.59 304.0 methowphenyl)acrylamide N—((1-Cyan0pyrrolidin 33 meethyD(4- D 2.87 325.1 , fluorophenyDnicotinamide Example 34 (S)-N-((1-Cyan0pyrrolidinyl)methyl)0x0-3,4-dihydr0-2H—benzofi][1,4]0xazine-6— carboxamide T "30’" The title compound was sised by a ure r to Example 20. LCMS: Method B, 2.80 min, MS: ES+ 301.27, 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.85 (s,1 H), 8.52 (t, J=5.6 Hz 1 H), 7.40 - 7.44 (m, 2 H), 7.00 (d, J=8.0 Hz, 1 H), 4.63 (s, 2 H), 3.36 - 3.44 (m, 3 H), 3.23 - 3.28 (m, 2 H), 3.13 - 3.21 (m, 1 H), 2.51 - 2.54 (m, 1 H), 1.91 - 1.95 (m, 1 H), 1.63 - 1.67 (m, 1 H).
Example 35 (R)-6—Ch10r0-N-((1 -cyan0pyrr01idinyl)methyl)imidazo[1,2-a]pyridinecarboxamide The title compound was synthesised by a procedure similar to Example 20. LCMS: Method A, 3.23 min, MS: ES+ 303.94, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.88 (m, 1 H), 8.72 (t, J=6.0Hz, 1 H), 8.33 (s, 1 H), 7.64 (d, J=9.6 Hz, 1 H), 7.41 (dd, J=2.0 Hz, 9.6 Hz, 1 H), 3.39 - 3.46 (m, 2 H), 3.26 - 3.31 (m, 2 H),3.16 - 3.19 (m, 1 H), 2.53 - 2.54 (m, 2 H), 1.87 - 1.96 (m, 1 H), 1.65 - 1.71 (m, 1 H).
Example 36 (R)-N-((1-Cyan0pyrr01idinyl)methpryrazolo[1,5-a]pyridinecarboxamide N—N "MC 2NH The title compound was synthesised by a procedure similar to Example 20. LCMS: Method A, 3.07 min, MS: ES+ 27009, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.70 (t, J=6.0 Hz, 1 H), 8.67 (dd, J=0.8 Hz, 6.8 Hz, 1 H), 7.77 (d, J=8.8 Hz, 1 H), 7.27 - 7.32 (m, 1 H), 7.02 - 7.05 (m, 1 H), 6.99 (s, 1 H), 3.40 - 3.46 (m, 2 H), 3.28 - 3.32 (m, 2 H), 3.17 - 3.20 (m, 1 H), 2.52 - 2.55 (m, 2 H), 1.89 - 1.97 (m, 1 H), 1.64 - 1.72 (m, 1 H). e 55 (3-Chlor0phenyl)-N-((1-cyan0pyrr01idinyl)methinsoxazolecarboxamide O O O WWa b, c \ 4* Wu CH\ "'-- 4* \ ""- N N Mn chNN CI CI CI Step a. To a stirred solution of 3-(3-chlorophenyl)isoxazolecarboxylic acid (CAS Number 100517- 43-9, 0.200 g, 0.894 mmol) and tert-butyl (R)(aminomethyl)pyrrolidinecarboxylate (CAS Number 1991743, 0.179 g, 0.894 mmol) in THF (2 ml) was added HATU (0.510 g, 1.34 mmol) and DIPEA (0.45 ml, 2.68 mmol) at rt. The reaction mixture was d at rt for 16 h. The resulting reaction mixture was diluted with water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (35% EtOAc in hexane) ng tert-butyl (R)((3- (3-chlorophenyl)isoxazolecarboxamido)methyl)pyrrolidinecarboxylate (0.250 g, 0.615 mmol).
LCMS: Method C, 2312 min, MS: ES+ 406.42 Steps b, c. The title compound was synthesised following the procedure described in Example 9, steps c, d. LCMS: Method A, 4.165 min, MS: ES+ 331.15, 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.21 (t, J=1.6 Hz, 1 H), 8.00 (t, J=1.6 Hz, 1 H), 7.90 - 7.93 (m, 1 H), 7.73 (s, 1 H), 7.56 - 7.64 (m, 2 H), 3.39 - 3.46 (m, 2 H), 3.35 - 3.38 (m, 1 H), 3.30 - 3.33 (m, 3 H), 3.15 - 3.28 (m, 1 H), 1.85 - 2.01 (m, 1 H), 1.62 - 1.71 (m, 1H). 36 HH 3 mH>H . .
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Step b. To a on of tert-butyl 3-(methylcarbamoyl)pyrrolidinecarboxylate (33.0 mmol) in THF (75 ml) was added BH3.THF (99.0 mmol) at 0°C. The reaction was d at 0°C for 3h. The resulting mixture was quenched by addition MeOH 20 ml. The resulting mixture was concentrated under reduced pressure, and then the residue was purified by column chromatography (SiOz, DCMzMeOH 100:0 to 10: 1) yielding tert-butyl 3-(methylcarbamoyl)pyrrolidinecarboxylate (12 mmol). 1H NMR (400 MHz, DMSO-d6) 5 345-38 (s, 2 H), 3.25-3.42 (m, 2H), 3.12-3.25 (m, 1 H), 2.85-2.91 (m, 1 H), 2.41-2.49 (m, 2 H), 2.12-2.35 (m, 3 H), 1.78-1.95 (s, 1 H), 1.45 — 1.61 (m, 2 H), 1.39 (s, 9 H).
Step c. To a solution of 2-([1,1'-biphenyl]—4-yl)acetic acid (0.2 mmol) in DCM (1 ml) was added HATU (0.2 mmol). The reaction mixture was stirred at 0°C for 20 min. Tert-butyl 3-((methylamino) methyl)pyrrolidine-l-carboxylate (0.2 mmol) and DIPEA (0.6 mmol) were added to the on mixture at rt and stirred for 16h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PEzEtOAc 1:2) yielding tert-butyl ([1,1'-biphenyl]- 4-yl)-N-methylacetamido)methyl)pyrrolidinecarboxylate. MS: ES+ 409.5.
Steps (1, e. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 1, steps b, c to provide the title compound (46.60 mg, 0.139 mmol).
LCMS: Method E, 2.90 min, MS: ES+ 334.2.
Example 38 N-((1-Cyan0pyrrolidinyl)methyl)pheny10xazolecarboxamide O O O aY b C 0% d, e O Ok a QXWNAO"a Gm" MEMONH2 O 0% 4. QXINOWJLHEN/m Step a. To a solution of 2-aminophenylethanone hydrochloride (0.50 g, 2.91 mmol) in DCM (5 ml) was added TEA (0.58 g, 5.83 mmol) at 0°C. The reaction mixture was d at 0°C for 15 min.
Ethyl chlor00Xoacetate (0.44 g, 3.21 mmol) was added slowly to the reaction mixture at 0°C. The reaction mixture was stirred at rt for 36 h. The resulting reaction mixture was poured into saturated NaHC03 solution (10 m1) and extracted with DCM (2 X 10 ml). The combined organic phase was collected and washed with brine (10 m1), dried over Na2SO4, d and concentrated under reduced pressure yielding ethyl 2-0Xo((2-0Xopheny1ethy1)amino)acetate (0.58 g, 2.46 mmol). LCMS: Method C, 1.79 min, MS: ES+ 236.33.
Step b. A solution of ethyl 2-0Xo((2-0Xopheny1ethy1)amino)acetate (0.58 g, 2.47 mmol) in POC13 (5 ml) was refluxed at 105°C for 2 h. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was carefiilly treated with saturated Na2C03 solution (20 m1) and the e was extracted with DCM (2 X 15 ml). The combined organic phase was collected and washed with brine (10 m1), dried over Na2SO4, filtered and concentrated under reduced pressure yielding ethyl 5-phenyloxazolecarboxylate (0.48 g, 2.211 mmol). LCMS: Method C, 2.09 min, MS: ES+ 218.18.
Step c. To a solution of ethyl 5-pheny10Xazolecarboxy1ate (0.46 g, 2.12 mmol) in THF (5 ml) was added DIPEA (0.82 g, 6.35 mmol) at 0°C and stirred for 15 min. Tert-butyl 3- (aminomethy1)pyrrolidinecarboxy1ate (0.53 g, 2.64 mmol) was added to the reaction e at 0°C followed by slow addition of TMA (2 M in toluene; 5.29 ml, 10.6 mmol) at 0°C. The resulting reaction mixture was heated at 70°C for 5 hr. The resulting reaction mixture was quickly poured into ice cold water (25 m1) and d through celite hyfiow. The filtrate was ted with EtOAc (3 X 15 ml). The combined organic phase was collected and washed with brine (10 m1), dried over Na2SO4, filtered and concentrated under d pressure yielding tert-butyl 3-((5-phenyloxazole carb0Xamido)methy1)-pyrrolidinecarboxy1ate (0.25 g, 0.673 mmol). LCMS: Method C, 2.28 min, MS: ES+ 372.4.
Steps (1, e. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 9, steps c, d and d by flash chromatography (35% - 40% EtOAc in ). The obtained sticky residue was triturated with pentanezdiethyl ether (2: 1, 2 m1) and dried to yield the title compound (0.013 g, 0.044 mmol). LCMS: Method B, 3.49 min, MS: ES+ , 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.17 (t, 5.6 Hz, 1H), 7.92 (s, 1 H), 7.83 (d, J=7.6 Hz, 2 H), 7.53 (t, J=7.2 Hz, 2 H), 7.43 —7.47 (m, 1H), 3.41 - 3.46 (m, 2 H), 3.34 - 3.38 (m, 2 H), 3.27 - 3.30 (m, 2 H), 3.16 —3.20 (m, 1 H), 1.91 - 1.99 (m, 1 H), 1.65 - 1.70 (m, 1H).
Example 66 (R)(2-Chlor0phenyl)-N-((1-cyan0pyrr01idinyl)methinsoxazolecarboxamide CI CI b CI 0 CI 0 a 0 —> —> / \ —> \ O N—OH N‘O N ‘0 CI 0 CI O e, f ‘Q Step a. To a stirred solution of 2-chlorobenzaldehyde (1.500 g, 10.67 mmol) in MeOH (10 ml) was added TEA (3.23 g, 32.0 mmol) at It. Hydroxylamine hydrochloride (0.889 g, 12.8 mmol) was added portion wise to the reaction mixture at It. The reaction mixture was stirred at rt for 4 h. The resulting mixture was concentrated under reduced pressure and the obtained e was diluted with ice cold water (50 ml). The obtained precipitates were collected by filtration and washed with chilled water (20 ml). The resulting solid material was dried under vacuum yielding 2-chlorobenzaldehyde oxime (1.250g 8.062 mmol). This al was directly used for next step without any filI'tl’lCl‘ purification.
LCMS: Method C, 1.803 min, MS: ES+ 156.24.
Step b. To a stirred solution of methyl propiolate (1.085 g 12.90 mmol) in water (10 ml) was added KCl (0.384 g, 5.16 mmol) and 2-chlorobenzaldehyde oxime (0.800g 5.16 mmol) at It. The reaction mixture was stirred at rt for 30 min. Oxone (2.376 g, 7.74 mmol) was added to the reaction mixture at It. The reaction mixture was stirred at rt for 4 h. The resulting mixture was diluted with water (25 ml) and ted with DCM (2 X 25 ml). The combined organic layer was washed with brine on (10 ml), dried over NaZSO4, filtered and concentrated under d pressure. The resulting residue was purified by flash column chromatography (5% EtOAc in hexane) yielding methyl 3-(2- chlorophenyl)isoxazole-5 -carboxylate (0.750 g, 3.164 mmol). LCMS: Method C, 2.139 min, MS: ES- 236.00.
Step c. To a stirred solution of methyl 3-(2-chlorophenyl)isoxazolecarboxylate (0.750 g, 3.16 mmol) in THszater (1:1, 6 ml) was added 20 (0.398 g, 9.49 mmol) at rt. The reaction mixture was stirred at rt for 1 h. The resulting reaction mixture concentrated under vacuum, diluted with ice cold water (10 ml) and ed using 1 M HCl solution. The resulting itates were collected by filtration. The obtained solid material was dried under high vacuum yielding 3-(2-chloro- phenyl)isoxazolecarboxylic acid (0.420 g, 1.88 mmol). This material was directly used for next step without any filI'tl’lCl‘ ation. LCMS: Method C, 1.475 min, MS: ES- 222.21.
Step d. To a stirred solution of 3-(2-chlorophenyl)isoxazolecarboxylic acid (0.220 g, 0.986 mmol) and tert-butyl (R)(aminomethyl)pyrrolidinecarboxylate (CAS Number 1991743, 0.197 g, 0.986 mmol) in DCM (3 ml) was added pyridine (0.778 g, 0.986 mmol) at 0°C, followed by dropwise addition of POC13 (0.226 g, 1.48 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min.
The resulting mixture was diluted with ice cold NaHC03 solution (30 ml) and extracted with DCM (2 x 20 ml). The ed organic layer was dried over NaZSO4, filtered and trated under reduced pressure. The resulting e was purified by flash column chromatography (1-2% MeOH in DCM) ng tert-butyl (R)-3 -((3 -(2-chlorophenyl)isoxazole-5 -carboxamido)methyl)pyrrolidine carboxylate (0.180 g, 0.443 mmol). LCMS: Method C, 2.179 min, MS: ES- 404.43.
Steps e, f. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 9, steps c, d. LCMS: Method A, 3.979 min, MS: ES+ 33095, 1H NMR (400 MHz, CDC13)5 ppm 7.73 - 7.75 (m, 1 H), 7.53 - 7.56 (m, 1 H), 7.44 - 7.48 (m, 1 H), 7.39 - 7.43 (m, 2 H), 6.88 (br s, 1 H), 3.45 - 3.63 (m, 5 H), 3.23 - 3.28 (m, 1 H), 2.61 - 2.69 (m, 1 H), 2.09 - 2.16 (m, 1 H), 1.77 - 1.84 (m, 1 H).
Example 67 (R)(4-Chlor0phenyl)-N-((1-cyan0pyrr01idinyl)methinsoxazolecarboxamide \ H N‘o CN TN The title compound was synthesised by a procedure r to Example 66. LCMS: Method A, 4.200 min, MS: ES+ 331.02, 1H NMR (400 MHz, CDC13)5 ppm 7.73 - 7.75 (m, 1 H), 7.53 - 7.56 (m, 1 H), 7.44 - 7.48 (m, 1 H), 7.39 - 7.43 (m, 2 H), 6.88 (br s, 1 H), 3.45 - 3.63 (m, 5 H), 3.23 - 3.28 (m, 1 H), 2.61 - 2.69 (m, 1 H), 2.09 - 2.16 (m, 1 H), 1.77 - 1.84 (m, 1 H).
Example 68 (R)(3-Cyan0phenyl)-N-((1 -cyan0pyrr01idinyl)methyU-I, 3, 4-0xadiazole carboxamide O O O O N\ a N\ b 0% /\ C O \ \ O O o/\ / 4’ ,NH2 4’ N\ I 0 fl 4’ \ \ ,NH N—N H // o o 0% 0% O /I:._ e,f CN’EN /I.,_ < \ I H <7 \ l H N‘N N‘N CN'§o // // N N Step a. To a stirred solution of methyl 3-cyanobenzoate (CAS Number 135311, 4.000 g, 24.84 mmol) in MeOH (40 ml) was added hydrazine hydrate (3.1 ml, 62.0 mmol) at 0°C. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was concentrated under vacuum, diluted with water (200 ml) and extracted with DCM (2 x 200 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was d by flash column chromatography (70% EtOAc in hexane) yielding obenzohydrazide (3.200 g, 19.87 mmol). LCMS: Method C, 0.934 min, MS: ES+ 16236, 1H NMR (400 MHz, DMSO- d6) 5 ppm 9.99 (s, 1 H), 8.21 (s, 1 H), 8.13 (d, J = 7.6 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.69 (t, J = 8.0 Hz, 1 H), 4.58 (s, 2 H).
Step b. To a stirred solution of 3-cyanobenzohydrazide (2.500 g, 15.52 mmol) in DCM (50 ml) was added TEA (13.1 ml, 93.2 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 min before dropwise addition of ethyl chlorooxoacetate (3.8 ml, 34.2 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was diluted with water (200 ml) and extracted with DCM (2 x 200 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under d pressure yielding ethyl 2-(2-(3 -cyanobenzoyl)hydrazinyl)oxoacetate (4.000 g, 15.32 mmol). This material was directly used for next step without any fimher purification. LCMS: Method C, 1.405 min, MS: ES- .
Step c. To a stirred solution of ethyl 2-(2-(3-cyanobenzoyl)hydrazinyl)oxoacetate (4.00 g, 15.32 mmol) in DCM (50 ml) was added TEA (6.8 ml, 48.6 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 min before addition of 4-toluenesulfonyl chloride (4.60 g, 34.2 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was diluted with water (200 ml) and ted with DCM (2 x 200 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting e was d by flash column chromatography (25% EtOAc in hexane) ng ethyl 5-(3-cyanophenyl)-1,3,4-oxadiazole carboxylate (2.20 g, 9.05 mmol). LCMS: Method C, 1.738 min, MS: ES+ 244.32.
Step (1. To a stirred solution of 5-(3-cyanophenyl)-1,3,4-oxadiazolecarboxylate (0.280 g, 1.152 mmol) and tert-butyl (R)(aminomethyl)pyrrolidinecarboxylate (CAS Number 1991743, 0.345 g, 1.728 mmol) in THF (2.5 ml) was drop wise added a solution of TBD (0.313 mg, 2.304 mmol) in THF (2.5 ml) at 0°C. The reaction e was stirred at rt for 3 h. The resulting reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under d pressure. The resulting residue was d by flash column chromatography (55% EtOAc in hexane) yielding tert-butyl (R)((5 -(3 -cyanophenyl)-1,3 ,4-oxadiazolecarboxamido)-methyl)pyrrolidinecarboxylate (0.3 05 g, 0.768 mmol). LCMS: Method C, 1.890 min, MS: ES+ 398.50.
Step e. A stirred solution of tert-butyl (R)((5-(3-cyanophenyl)-1,3,4-oxadiazolecarboxamido)- methyl)pyrrolidinecarboxylate (0.305 g, 0.768 mmol) in DCM (7 ml) was added TFA (0.91 ml) at It. The on mixture was stirred at rt for 40 min. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was re-distilled with DCM ( 3 X 5 ml) and dried under high vacuum yielding (R)-5 -(3 -cyanophenyl)-N-(pyrrolidin-3 -ylmethyl)-1,3 ,4-oxadiazole carboxamide TFA salt (0.290 g, 0.705 mmol). LCMS: Method C, 1.345 min, MS: ES+ 298.46.
Step f. To a solution of (R)(3-cyanophenyl)-N-(pyrrolidin-3 -ylmethyl)-1,3,4-oxadiazole carboxamide TFA salt (0.290 g, 0.705 mmol) in THF (7 ml) was added K2C03 (0.292 g, 2.12 mmol) at It. The reaction mixture was stirred at rt for 10 min. Cyanogen bromide (0.074 g, 0.705 mmol) was added to the reaction e at 0°C. The reaction mixture was d at rt for 45 min. The resulting mixture was poured into water (25 ml) and the obtained precipitates were collected by filtration and wash with water (25 ml). The obtained solid al was triturated using pentane (2 x 6 ml) and dried under vacuum yielded title compound (0.160 g, 0.480 mmol). LCMS: Method A, 2.965 min, MS: ES+ 340.10 [M+18+H+], 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.55 (t, J: 6.0 Hz, 1 H), 8.50 (s, 1 H), 8.40 (d, J: 8.0 Hz, 1 H), 8.16 (d, J: 8.0 Hz, 1 H), 7.86 (t, J: 6.0 Hz, 1 H), 3.42 - 3.48 (m, 3 H), 3.33 - 3.39 (m, 2 H), 3.17 - 3.21 (m, 1 H), 2.52 - 2.55 (m, 1 H), 1.95 - 2.01 (m, 1 H), 1.67 - 1.74 (m, 1 H).
Example 69 (S)(3-Cyan0phenyl)-N-((1 -cyan0pyrr01idinyl)methyU-I, 3, iazole amide 9%0%.N—N ufijwéw N// The title compound was synthesised by a procedure similar to Example 68. LCMS: Method A, 3.071 min, MS: ES+ 340.10 [M+18+H+], 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.55 (t, J: 6.0 Hz, 1 H), 8.50 (s, 1 H), 8.40 (d, J: 8.0 Hz, 1 H), 8.16 (d, J: 8.0 Hz, 1 H), 7.86 (t, J: 6.0 Hz, 1 H), 3.42 - 3.48 (m, 3 H), 3.33 - 3.39 (m, 2 H), 3.17 - 3.21 (m, 1 H), 2.52 - 2.55 (m, 1 H), 1.95 - 2.01 (m, 1 H), 1.67 - 1.74 (m, 1 H).
Example 70 (R)-N-((1-Cyan0pyrr01idinyl)methyU-I-phenyl-1H—imidazolecarboxamide o o o a b c_e o / —» / —» —» \ /I... 0 O \;N ON \\;N ON/YLOH\;N ON/EJLH\sN CN’ZN Step a. To a stirred solution of methyl 4-imidazolecarboxylate (CAS Number 173257, 0.500 g, 3.97 mmol) and 1,10-phenanthroline (1.400 g, 7.94 mmol) in DMSO (5 ml) was added iodobenzene (1.600 g, 7.94 mmol), Cs2C03 (3.800 g, 11.9 mmol) and Cu20 (0.567 g, 3.97 mmol) at rt in a microwave tube. The reaction mixture was heated at 100°C for 15 min in microwave. The resulting reaction mixture was cooled to rt and filtered. The obtained filtrate was diluted with water (60 ml) and ted with EtOAc (3 x 60 ml). The combined organic layer was dried over Na2SO4, filtered and trated under reduced pressure yielding methyl 1-phenyl-1H-imidazolecarboxylate (0.450 g, 2.23 mmol). This material was directly used for next step without any fithher purification. LCMS: Method C, 2.066 min, MS: ES+ .
Step b. To a stirred solution of methyl 1-phenyl-1H-imidazolecarboxylate (0.450 g, 2.23 mmol) in THszater (9:1, 10 ml) was portion wise added NaOH (0.267 g, 6.68 mmol) at 0°C. The reaction mixture was stirred at rt for 16 h. The resulting mixture was diluted with ice cold water (60 ml) and acidified using 1 M HCl solution. The resulting mixture was ted with EtOAc (3 x 60 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 1-phenyl-1H-imidazolecarboxylic acid (0.230 g, 1.22 mmol). This material was directly used in the next step withoutfithher purification. LCMS: Method C, 1.357 min, MS: ES+ 189.20.
Steps c-e. The title compound was synthesised from the intermediate above using a procedure similar to that described for e 55. LCMS: Method B, 3.155 min, MS: ES+ 29643, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.40 (s, 1 H), 8.37 (s, 1 H), 8.25 (s, 1 H), 7.73 - 7.75 (m, 2 H), 7.52 - 7.56 (m, 2 H), 7.41 - 7.43 (m, 1 H), 3.37 - 3.44 (m, 4 H), 3.24 - 3.28 (m, 2 H), 3.15 - 3.19 (m, 1 H), 1.89 - 1.94 (m, 1 H), 1.64 - 1.69 (m, 1 H).
Example 71 (R)(3-Cyan0phenyl)-N-((1-cyan0pyrrolidinyl)methyl)-1H—imidazole carboxamide O O O a N’YLO/ b N/YLOH 4,c-e /I... \ 0/ 4. 4. NVLH HN \sN \SN \SN CN—EN \SN // // // N N Step a. To a stirred solution of methyl 4-imidazolecarboxylate (CAS Number 26-7, 1.000 g, 7.93 mmol) and 3-iodobenzonitrile (CAS Number 691133, 1.990 g, 8.72 mmol) in DMSO (15 ml) was added L-proline (0.180 g, 1.57 mmol), K2C03 (2.290 g, 16.65 mmol) and CuI (0.154 g, 0.79 mmol) in a sealed tube. The reaction mixture was heated at 90°C for 16 h. The resulting reaction mixture was cooled to rt, d with water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated using MTBE (3 x 10) and resulting material was dried under vacuum yielding methyl yanophenyl)-1H-imidazolecarboxylate (0.400 g, 1.76 mmol). This material was directly used for next step without any fithher purification. LCMS: Method C, 1.483 min, MS: ES+ 228.36, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.64 (s, 1 H), 8.51 (s, 1 H), 8.38 (s, 1 H), 8.15 (dd, 1: 76,16 Hz, 1 H), 7.89 (d, J: 8.0 Hz, 1 H), 7.75 (t, J: 8.0 Hz, 1 H), 3.80 (s, 3 H).
Step b. To a solution of methyl 1-(3-cyanophenyl)-1H-imidazolecarboxylate (0.400 g, 1.76 mmol) in THszater (9:1, 10 ml) was portion wise added NaOH (0.211 g, 5.18 mmol) at It. The reaction mixture was stirred at rt for 2 h. The resulting mixture diluted with water (30 ml) and extracted with EtOAc (2 x 50 ml). The aqueous layer was acidified using 1 M HCl and the obtained itates were collected by ion and washed with hexane (10 ml). The obtained solid material was dried under high vacuum yielding 1-(3-cyanophenyl)-1H-imidazolecarboxylic acid (0.250 g, 1.173 mmol).
This material was directly used for next step without any filI'tl’lCl‘ purification. LCMS: Method C, 1.343 min, MS: ES+ .
Steps c-e. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 55. LCMS: Method A, 2.673 min, MS: ES+ 321.10, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.50 (s, 1 H), 8.37 - 8.43 (m, 3 H), 8.14 (dd, J: 8.8, 1.6 Hz, 1 H), 7.87 (d, J: 8.8 Hz, 1 H), 7.74 (d, J: 8.0 Hz, 1 H), 3.31 - 3.46 (m, 4 H), 3.24 - 3.31 (m, 2 H), 3.15 - 3.19 (m, 1 H), 1.89 - 1.94 (m, 1 H), 1.64 - 1.69 (m, 1 H).
Example 72 (4-cyan0phenyl)-N-((1-cyan0pyrrolidinyl)methyl)-1H—imidazolecarboxamide N:\QNVLN/"-. \sN GWEN The title compound was synthesised by a procedure similar to Example 71. LCMS: Method A, 2.693 min, MS: ES+ 321.15, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.56 (d, J=1.6 Hz, 1 H), 8.44 - 8.45 (m, 1 H), 8.43 (d, J=1.2 Hz, 1 H), 8.00 - 8.06 (m, 4 H), 3.37 - 3.44 (m, 2 H), 3.24 - 3.31 (m, 2 H), 3.15 - 3.19 (m, 1 H), 2.51 - 2.53 (m, 2 H), 1.89 - 1.93 (m, 1 H), 1.64 - 1.69 (m, 1 H).
Example 73 (R)-N-((1-Cyan0pyrrolidinyl)methy!)(2-meth0xyphenyl)-1H—imidazole carboxamide The title compound was synthesised by a ure similar to Example 71. LCMS: Method A, 2.963 min, MS: ES+ 32620, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.33 (t, J: 6.0 Hz, 1 H), 7.98 (s, 1 H), 7.87 (s, 1 H), 7.44 - 7.48 (m, 2 H), 7.28 (d, J: 8.0 Hz, 1 H), 7.09 (d, J: 7.6 Hz, 1 H), 3.84 (s, 3 H), 3.49 - 3.51 (m, 4 H), 3.24 - 3.27 (m, 2 H), 3.15 - 3.19 (m, 1 H), 1.87 - 1.95 (m, 1 H), 1.59 - 1.71 (m, 1 Example 74 (R)-N-((1-Cyan0pyrrolidinyl)methy!)(3-meth0xyphenyl)-1H—imidazole carboxamide The title compound was synthesised by a procedure r to Example 71. LCMS: Method B, 3.202 min, MS: ES+ 32653, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.38 (d, J: 1.2 Hz, 1 H), 8.34 - 8.37 (m, 1 H), 8.28 (d, J=1.2 Hz, 1 H), 7.43 (t, J: 8.0 Hz, 1 H), 7.30 - 7.33 (m, 2 H), 6.97 (dd, J: 8.8, 2.0 Hz, 1 H), 3.85 (s, 3 H), 3.35 - 3.44 (m, 4 H), 3.25 - 3.28 (m, 2 H), 3.15 - 3.19 (m, 1 H), 1.89 - 1.94 (m, 1 H), 1.65 - 1.70 (m, 1 H).
Example 39 N-((1-Cyan0pyrrolidinyl)methyl)-6—(1-methyl-1H—pyrazolyl)imidazofl, 2- ajpyridine-Z-carboxamide O O O a b ‘1' \ / "CTNAHACN‘EN N‘ _ Step a. To a solution of 6-bromoimidazo[l,2-a]pyridinecarboxy1ic acid (CAS Number 749849 7, 1.0 g, 4.14 mmol) and tert-butyl 3-(aminomethyl)pyrrolidine-l-carboxylate (0.99 g, 4.97 mmol) in DMF (10 ml) were added DIPEA (1.1 ml, 6.22 mmol) and HATU (2.36 g, 6.22 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The ing reaction mixture was poured into water (200 m1) and ted with EtOAc (4 X 50 ml). The combined c phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (2-3% MeOH in DCM) yielding tert-butyl 3-((6-bromoimidazo[l,2- a]pyridinecarboxamido)methy1)pyrrolidine-l-carboxylate (1.75 g, 4.13 mmol). LCMS: Method C, 2.02 min, MS: ES+ 42332, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.94 (s, 1 H), 8.64 (t, J=6.0 Hz, 1 H), 8.30 (s, 1 H), 7.58 (d, J=9.6 Hz, 1 H), 7.47 (dd, J=9.6, 1.6 Hz, 1 H), 3.23 - 3.39 (m, 3 H), 3.16 - 3.21 (m, 2 H), 2.97 - 3.01 (m, 1 H), 2.42 - 2.47 (m, 1 H), 1.80 - 1.90 (m, 1 H), 1.54 - 1.65 (m, 1 H), 1.41 (s, 9 H).
Step b. To a solution of teIt-butyl 3-((6-bromoimidazo[1,2-a]pyridinecarboxamido)methyl) pyrrolidine-l-carboxylate (0.30 g, 0.70 mmol) and 1-methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H-pyrazole (0.17 g, 0.85 mmol) in 1,4-dioxane:water (9:1, 8 ml) was added K2C03 (0.195 g, 1.40 mmol) at rt. The reaction mixture was ed for 10 min before addition of Pd(PPh3)4 (0.04 g, 0.035 mmol). The reaction e was heated at 100°C for 16 h. The resulting reaction mixture was poured into water (150 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine solution (2 x 25 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (2-3% MeOH in DCM) yielding tert-butyl (1-methyl-1H-pyrazolyl)-imidazo[1,2-a]pyridine- oxamido)methyl)pyrrolidinecarboxylate (0.15 g, 0.35 mmol). LCMS: Method C, 1.93 min, MS: ES+ 425.75, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.83 (s, 1 H), 8.57 (t, J=6.00 Hz, 1 H), 8.25 (s, 1 H), 8.18 (s, 1 H), 7.88 (s, 1 H), 7.57 - 7.62 (m, 2 H), 3.89 (s, 3 H), 3.29 - 3.39 (m, 3 H), 3.17 - 3.21 (m, 2 H), 2.98 - 3.02 (m, 1 H), 2.42 - 2.47 (m, 1 H), 1.84 - 1.87 (m, 1 H), 1.54 - 1.61 (m, 1 H), 1.39 (s, 9 H).
Steps c, d. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 9, steps c, d and purified by column chromatography (2-3% MeOH in DCM) yielding the title compound (0.028 g, 0.08 mmol). LCMS: Method C, 1.64 min, MS: ES+ 350.74, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.83 (s, 1 H), 8.64 (t, J=6.4 Hz, 1 H), 8.26 (s, 1 H), 8.19 (s, 1 H), 7.88 (s, 1 H), 7.57 - 7.62 (m, 2 H), 3.89 (s, 3 H), 3.37 - 3.46 (m, 3 H), 3.27 - 3.33 (m, 2 H), 3.16 - 3.20 (m, 1 H), 2.51 - 2.55 (m, 1 H), 1.88 - 1.94 (m, 1 H), 1.64 - 1.72 (m, 1 H).
Example 75 (R)-N-((1-Cyan0pyrrolidinyl)methyl)(1H—pyrazolyl)imidazofl,2-a]pyridine carboxamide N/YL /I. \ N ., — Example 76 (R)-N-((1-Cyan0pyrrolidinyl)methyl)(1H—pyrazolyl)imidazofl,2-a]pyridine carboxamide SAN"- WN CN2N H N~N _ The title nd was synthesised by a procedure similar to Example 39. LCMS: Method A, 2.845 min, MS: ES+ 33601, 1H NMR (400 MHz, DMSO-d6) 5 ppm 13.02 (s, 1 H), 9.02 (s, 1 H), 8.64 (t, J=6.0 Hz, 1 H), 8.34 (s, 1 H), 7.80 - 7.84 (m, 1 H), 7.47 - 7.61 (m, 2 H), 6.72 (s, 1 H), 3.36 - 3.42 (m, 3 H), 3.27 - 3.33 (m, 2 H), 3.14 - 3.17 (m, 1 H), 2.54 - 2.56 (m, 1 H), 1.87 - 1.91 (m, 1 H), 1.63 - 1.69 (m, 1 H).
Example 77 (R)-N-((1-Cyan0pyrr01idinyl)methyl)-7—cyclopr0pylimidazo[1,2-a]pyridine carboxamide The title compound was synthesised by a procedure similar to Example 39. LCMS: Method B, 2.675 min, MS: ES+ 31058, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.53 (br s, 1 H), 8.41 (d, J=6.4 Hz, 1 H), 8.21 (s, 1 H), 7.25 (s, 1 H), 6.62 (d, J=6.4 Hz, 1 H), 3.32 - 3.37 (m, 2 H), 3.22 - 3.26 (m, 2 H), 3.14 - 3.16 (m, 1 H), 2.49 - 2.53 (m, 2 H)1.99 - 2.01 (m, 1 H), 1.87 - 1.89 (m, 1 H), 1.63 - 1.66 (m, 1 H), 0.98 - 1.00 (m, 2 H), 0.72 - 0.79 (m, 2 H).
Example 40 1-Benzyl-N-((1-cyan0pyrrolidinyl)methy!)methyl-IH—pyrazolecarb0xamide ,1 61,11,691 €1,131 61,13 Step a. To a solution of ethyl 3-methyl-1H-pyrazole-5 -carboxylate (CAS Number 40270, 1.50 g, 9.73 mmol) in THF (20 ml) was added KOH (0.65 g, 11.67 mmol) at It. The reaction mixture was stirred at rt for 45 min. Benzyl bromide (1.16 ml, 9.73 mmol) was added dropwise to the reaction mixture at rt. The resulting on mixture was stirred at 70°C for 16 h. The e was then poured into water (50 ml) and extracted with EtOAc (2 x 50 ml) and the combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The ing residue was purified by column chromatography (18% EtOAc in hexane) yielding ethyl 1-benzylmethyl-1H- lecarboxylate (1.4 g, 5.734 mmol) LCMS: Method C, 2.27 min, MS: ES+245.4.
Step b. To a solution of ethyl 1-benzylmethyl-1H-pyrazolecarboxylate (1.4 g, 5.73 mmol) in THF: water (16 ml: 4 ml) was added LiOH (1.20 g, 28.65 mmol) at It. The reaction mixture was stirred at 50°C for 16 h. The resulting reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The s layer was ed using 1 M aqueous solution of HCl (5 ml) and extracted into EtOAc (2 x 50 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 1-benzylmethyl-1H-pyrazole carboxylic acid (1.10 g, 5.09 mmol). This material was directly used for the next step without further purification. LCMS: Method C, 1.89 min, MS: ES+ 217.29.
Steps c-e. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 20, steps a-c. LCMS: Method B, 3.68 min, MS: ES+ 3246, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.29 (t, J=6 Hz, 1 H), 7.26 - 7.37 (m, 3 H), 7.11 (d, J = 7.2 Hz, 2 H), 6.47 (s, 1 H), 5.36 (s, 2 H), 3.29 - 3.43 (m, 3 H), 3.20 (t, J = 6.4 Hz, 2 H), 3.12 - 3.16 (m, 1 H), 2.42 - 2.46 (m, 1 H), 2.21 (s, 3 H), 1.85 - 1.93 (m, 1 H), 1.59 - 1.68 (m, 1 H).
Example 78 (R)Benzyl-N-((1-cyan0pyrrolidinyl)methy!)-1H—imidazolecarboxamide O O H’LOA a A b O C O \ 0% I + \ N O/\ N/lll' N N H Chi—Q Step a. A mixture of tert-butoxybis(dimethylamino)methane (CAS Number 58157, 3.500 g, 20.11 mmol) and ethyl isocyanoacetate (CAS Number 29994, 2.270 g, 20.11 mmol) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (15% EtOAc in hexane) yielding 1-(dimethylamino) ethoxy-N-methylidyneoxopropenaminium (1.900 g, 11.24 mmol). LCMS: Method C, 1.570 min, MS: ES+ 169.43 Step b. A mixture of 1-(dimethylamino)ethoxy-N-methylidyne-3 -oxopropenaminium (0.500 g, 2.98 mmol) and benzylamine (1.500 g, 14.9 mmol) was heated at 90°C for 2 h. The resulting reaction e was cooled to It, diluted with water (20 ml) and ted with EtOAc (3 x 50 ml).
The combined organic layer was washed with brine solution (20 ml), dried over Na2SO4, filtered and concentrated under d pressure yielding ethyl 1-benzyl-1H-imidazolecarboxylate (0.530 g, 2.30 mmol). This material was directly used for next step without any fithher purification. LCMS: Method C, 1.580 min, MS: ES+ 231.36 Step c. To a stirred solution of ethyl 1-benzyl-1H-imidazolecarboxylate (0.350 g, 1.52 mmol) and tert-butyl (R)(aminomethyl)pyrrolidinecarboxylate (CAS Number 1991743, 0.365 g, 1.826 mmol) in THF (5 ml) was added DIPEA (0.84 ml, 4.56 mmol) at rt. Trimethyl aluminium (2M in toluene; 3.8 ml, 7.6 mmol) was added dropwise to the reaction e at rt and then heated at 70°C for 16 h. The reaction mixture was cooled to It, diluted with water (20 ml) and NH4Cl solution (20 ml). The e was ted with EtOAc (3 x 50 ml) and the ed organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (2% MeOH in DCM) yielding utyl (R)((1-benzyl-1H- imidazolecarboxamido)methyl)pyrrolidinecarboxylate (0.410 g, 1.067 mmol). LCMS: Method C, 1.405 min, MS: ES+ 285.48 [M-100] Steps d, e. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 9, steps c, d. LCMS: Method A, 2.789 min, MS: ES+ 31010, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.19 (t, J: 6.0 Hz, 1 H), 7.85 (s, 1 H), 7.70 (s, 1 H), 7.31 - 7.39 (m, 5 H), 5.23 (s, 2 H), 3.33 - 3.43 (m, 3 H), 3.28 - 3.34 (m, 2 H), 3.11 - 3.21 (m, 1 H), 2.41 - 2.46 (m, 1 H), 1.83 - 1.92 (m, 1 H), 1.58 - 1.67 (m, 1 H).
Example 79 (R)-N-((1 -Cyan0pyrr01idinyl)methyU-I -(cyclopr0pylmethyl)-1H—imidazole carboxamide N/YLH\ /"'-CN—=N The title compound was synthesised by a procedure similar to Example 78. LCMS: Method B, 2.583 min, MS: ES+ 27448, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.16 (s, 1 H), 7.73 (s, 2 H), 3.84 - 3.86 (m, 2 H), 3.32 - 3.40 (m, 3 H), 3.15 - 3.22 (m, 3 H), 2.49 - 2.50 (m, 1 H), 1.87 - 1.90 (m, 1 H), 1.62 - 1.70 (m, 1 H), 1.18 - 1.22 (m, 1 H), 0.50 - 0.60 (m, 2 H), 0.34 - 0.40 (m, 2 H).
Example 41 1-(3-Chlor0phenyl)((1-cyan0pyrrolidinyl)methyl)urea HerN—é‘é- 4» O O a CI/QHJLHACN‘Q Lto ol/QHJLHENIZN Step a. To a on of 1-chloroisocyanatobenzene (0.2 mmol) in DCM (1 mL) was added tertbutyl 3-(aminomethyl)pyrrolidinecarboxylate (0.2 mmol) and DIPEA (0.6 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated under d pressure and the resulting residue was purified by prep-TLC (PEzEtOAc 1:2) yielding tert-butyl 3-((3-(3- phenyl)ureido)methyl)-pyrrolidinecarboxylate. MS: ES+ 354.8.
Step b, c. The title compound was synthesised from the intermediate above using a procedure similar to that described for Example 1, steps b, c to provide the title compound (5.03 mg, 0.018 mmol).
LCMS: Method E, retention time 2.56 min, MS: ES+ 279.0.
Compounds in Table 4 were sised using a procedure similar to that described for Example 41. $0 R R NTC _, JL H HEN—EN Table 4 LCMS LCMS RT MS EX R Name Method (min) ES+ 1-((]-Cyan0pyrrolidin 42 " meethyD(2-flu0r0 F 2.30 277.0 methylphenyDurea D 1-(3-BenzylphenyD(fl- 43 E 2'85 335'0 cyanopyrrolidinyl)methyl)urea Cl Cyan0pyrrolidin 44 _— meethyD(2,4- E 3.09 313.0 CI dichlorophenyl)urea 1-((]-Cyan0pyrrolidin 45 meethyD(4- E 2.90 313.0 F CQ—3 (Wifluoromethybphenyl)urea Example 46 N-((1 -Cyan0pyrr01idinyl)methyl)-N-methyl(2-methylthiazolyl)- benzenesulfonamide O ab 1 a S )KCN—Qo ’ o o ——<\ | otsgo Ho fl M3 N 0% I —<0 m:I N— Step c. To a solution of 3-(2-methy1thiazolyl)benzenesulfonyl chloride (0.2 mmol) in DCM (1 ml) was added tert-butyl 3-((methy1amino)methyl)pyrrolidinecarboxylate (0.2 mmol) and DIPEA (0.6 mmol). The reaction mixture was stirred at rt for 16 h. The resulting mixture was concentrated under reduced pressure and the e was purified by prep-TLC (PEzEtOAc 1:2) ng tert-butyl 3 -((N-methyl-3 -(2-methylthiazolyl)pheny1sulfonamido)methyl)pyrrolidinecarboxylate. MS: ES+ 452.6.
Steps (1, e. The title nd was synthesised from the intermediate above using a procedure similar to that described for Example 1, steps b, c to provide the title compound (2.0 mg, 0.005 mmol).
LCMS: Method E, ion time 2.82 min, MS: ES+ 377.1.
Example 47 N-((1-Cyan0pyrrolidinyl)methyl)-N-methyl((5-(trifluoromethyUpyridin-Z— yl)0xy)benzenesulf0namide F O:S¢O F \ ‘N u Q on_=—~ N o The title compound was synthesised by a procedure similar to Example 46, steps c-e. LCMS: Method E, 3.11 min, MS: ES+ 441.0.
Example 48 3-(1 -((6-(5-Methylisoxazolyl)benzo[d]:hiazolyl)amin0)ethyUpyrrolidine-I - carbonim'le HOXC "<0 0 N _. )KC "<0 —» N N SA 04— o o H N—Qo N’ "V, A <— A AC s S 0%— _. N H N—f.N H N Step a. To a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidinecarboxylic acid (3.0 g, 13.94 mmol) in DCM (70 ml) was added CDI (2.2 g, 13.94 mmol) at rt. The reaction mixture was stirred at rt for 1 h. N,O-Dimethyl ylamine HCl (2.4 g, 245.1 mmol) was added at rt. The resulting mixture was stirred at rt for 16 h. The reaction mixture was poured into water (300 ml) and extracted with DCM (2 x 100 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure ng tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine ylate (4.0 g, quantitative). This material was used for the next step without further purification.
LCMS: Method C, 1.91 min, MS: ES+ 25931, 1H NMR (400 MHz, DMSO-d6) 5 ppm 3.69 (s, 3 H), 3.44 - 3.50 (m, 3 H), 3.19 - 3.28 (m, 2 H), 3.11 (s, 3 H), 1.94 -2.08 (m, 1 H), 1.86 - 1.91 (m, 1 H), 1.40 (s, 9 H).
Step b. A solution of utyl 3-(methoxy(methyl)carbamoyl)pyrrolidinecarboxylate (4.0 g, 15.50 mmol) in THF (70 ml) was stirred at 0°C under nitrogen. 3M CH3MgBr in diethyl ether (26 ml, 78 mmol) was added drop wise at 0°C. The reaction mixture was stirred at 0°C for 30 min. The resulting reaction mixture was poured into saturated ammonium chloride solution (1 L) and extracted with EtOAc (2 x 200 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl 3-acetylpyrrolidinecarboxylate (3.0 g, 14.08 mmol).
This material was used for the next step without fithher ation. LCMS: Method A, 3.83 min, MS: ES+ 157.89 (M-56), 1H NMR (400 MHz, 6) 5 ppm 3.77 - 3.40 (m, 2 H), 3.22 - 3.25 (m, 3 H), 2.17 (s, 3 H), 2.03 - 2.11 (m, 1 H), 1.85 - 1.94 (m, 1 H), 1.39 (s, 9 H).
Step c. To a stirred solution of teIt-butyl 3-acetylpyrrolidinecarboxylate (0.5 g, 2.347 mmol) and 2- aminobromobenzothiazole (0.43 g, 1.88 mmol) in THF (10 ml) was added titanium(IV) isopropoxide (3.33 g, 11.7 mmol) at 0°C. The on mixture was stirred at rt for 16 h. EtOH (4 ml) and sodium borohydride (0.26 g, 7.04 mmol) was added to the reaction mixture at 0°C. The on mixture was stirred at 80°C for 8 h. The resulting reaction e was poured into water (100 ml) and filtered through celite hyflow. The resulting filtrate was extracted with EtOAc (2 x 70 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure.
The resulting crude material was purified by flash tography (25% EtOAc in hexane) yielding teIt-butyl 3-(1-((6-bromobenzo[d]thiazolyl)amino)ethyl)pyrrolidinecarboxylate (0.18g, 0.423 mmol). LCMS: Method A, 5.57 min, MS: ES+ 425.8, 427.8.
Step d. A solution of teIt-butyl 3-(1-((6-bromobenzo[d]thiazolyl)amino)ethyl)pyrrolidine carboxylate , 0.352 mmol), 5-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)isoxazole (0.29 g, 1.41 mmol) and NaHC03 (0.148 g, 1.76 mmol) in DMF:water (4: 1, 5 ml) was stirred at rt in a microwaveable Vial. The mixture was degassed for 30 min before addition of Pd(dppf)C12 (0.025 g, 0.035 mmol) and the on mixture was heated to 90°C for 1 h in a microwave. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was dried over Na2SO4, filtered and trated under reduced pressure.
The crude material was purified by flash chromatography (30% EtOAc in hexane) yielding tert-butyl 3 -(1-((6-(5 -methylisoxazolyl)benzo[d]thiazolyl)amino)ethyl)pyrrolidinecarboxylate (0. 1 g, 0.233 mmol). LCMS: Method A, 4.95 min, MS: ES+ 429.10.
Steps e, f. The title compound was synthesised as mixture of reoisomers from the intermediate above using a procedure similar to that bed for Example 1, steps b, c to provide the title compound yielding (0.03 g, 0.084 mmol). LCMS: Method A, 4.10 min, MS: ES+ 354.0, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.83 (s, 1 H), 8.12 (d, J=8.4 Hz, 1 H), 7.85 (s, 1 H), 7.36 - 7.44 (m, 2 H), 3.96 - 4.06 (m, 1 H), 3.45 - 3.52 (m, 1 H), 3.14 - 3.21 (m, 1 H), 2.58 (s, 3 H), 2.41 - 2.46 (m, 2 H), 1.83 - 2.05 (m, 1 H), 1.55 - 1.65 (m, 1 H), 1.19 (d, J=6.4 Hz, 3 H).
Example 49 (6—(1H-Pyrazolyl)benzo[d]thiazol—2-yl)amino)ethyl)pyrr01idinecarb0nitrile WWWIN, SAHrCNéN The title compound was synthesised by a procedure similar to Example 48. LCMS: Method A, 3.32 min, MS: ES+ 338.9, 1H NMR (400 MHz, DMSO-d6) 5 ppm 12.86 (s, 1 H), 8.12 (s, 1 H), 7.99 (dd, J = 3, 8.4 Hz, 1 H), 7.91 (t, J = 2 Hz, 1 H), 7.88 (s, 1 H), 7.45 - 7.48 (m, 1 H), 7.33 (dd, J = 3, 8.4 Hz, 1 H), 3.94 - 3.98 (m, 1 H), 3.43 - 3.51 (m, 2 H), 3.13 - 3.22 (m, 2 H), 2.36 - 2.42 (m, 1 H), 1.95 - 2.01 (m, 1 H), 1.68 - 1.75 (m, 1 H), 1.17 - 1.23 (m, 3 H).
Example 50 3-(1-(Isoquinolinylamin0)ethyl)pyrr01idinecarb0nitrile \ MCI: The title compound was synthesised by a procedure similar to Example 48. LCMS: Method G, 24.90 min, 25.00 min, MS: ES+ 267.09, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.84 (s, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.51 -7.54 (m, 1 H), 7.43 - 7.47 (m, 1 H), 7.12 - 7.16 (m, 1 H), 6.611 (s, 1 H), 6.41 (d, J=8.8 Hz, 1 H), 3.88 - 3.97 (m, 1 H), 3.41 -3.53 (m, 2 H), 3.76 - 3.99 (m, 1 H), 3.12 - 3.20 (m, 1 H), 2.35 - 2.43 (m, 1 H), 1.97 - 2.02 (m, 1 H), 1.65 - 1.76 (m, 1 H), 1.30 - 1.67 (m, 3 H).
Example 51 3-((1-(1-Cyan0pyrr01idinyl)ethyDamino)isoquinoline-6—carbonim'le Br NH2 N4 NH2 N4 CI N’ H N—( Step a. To a solution of 1-(tert-butoxycarbonyl)pyrrolidinecarboxylic acid (3.00 g, 13.95 mmol) in DCM (70 ml) was added CDI (2.26 g, 13.95 mmol) at 0°C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was treated with N,O-dimethylhydroxylamine HCl (2.03 g, 2.09 mmol) and stirred for 12 h. The resulting on mixture was poured into water (50 ml) and ted with DCM (3 x 40 ml). The combined organic phase was collected, dried over NaZSO4, filtered and concentrated under reduced pressure yielding tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine carboxylate (3.20 g, 12.40 mmol). This material was directly used in the next step without fithher purification. LCMS: Method C, 1.90 min, MS: ES+ 259.40.
Step b. To a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidinecarboxylate (3.20 g, 12.4 mmol) in THF (40 ml) was added 3M solution of CH3MgBr in l ether (21.0 ml, 63 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0°C and quenched by se addition of water (50 ml) followed by addition of EtOAc (50 ml). The resulting reaction mixture was filtered through celite hyfiow and the celite bed was washed with EtOAc (3 x 20 ml). The filtrate was extracted with EtOAc (3 x 70 ml). The combined c phase was ted, dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting e was purified by column chromatography (5% MeOH in DCM) yielding tert-butyl 3-acetylpyrrolidine carboxylate (2.10 g, 9.84 mmol). LCMS: Method C, 1.93 min, MS: ES+ 214.30.
Step c. To a solution of tert-butyl 3-acetylpyrrolidinecarboxylate (0.70 g, 3.20 mmol) in MeOH (10 ml) was added ammonium e (0.91 g, 11.00 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. NaCNBH3 (0.60 g, 9.60 mmol) was added n wise to the reaction mixture at 0°C.
The reaction mixture was d at rt for 16 h. The resulting reaction mixture was concentrated under reduced pressure, diluted with water (150 ml) and extracted with EtOAc (2 x 20 ml). The combined organic phase was collected, dried over NaZSO4, filtered and concentrated under d pressure yielding tert-butyl 3-(1-aminoethyl)pyrrolidinecarboxylate (0.47 g, 2.19 mmol) as a mixture of diastereomers. This material was directly used for the next step without fithher purification. LCMS: Method A, 3.54 & 3.67 min, MS: ES+ 215.10.
Step d. To a solution of oisoquinolinamine (0.80 g, 3.59 mmol) in DMA (10 ml) was added 2 (2.09 g, 17.94 mmol) and Pd(PPh3)4 (1.24 g, 1.08 mmol). The reaction mixture was heated at 90°C for 1 h. The resulting mixture was poured into water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was d by column chromatography (28% EtOAc in hexane) yielding 3-aminoisoquinolinecarbonitrile (0.57 g, 3.37 mmol). LCMS: Method C, 1.58 min, MS: ES+ 17023, 1H NMR (400 MHz, 6) 5 ppm 8.94 (s, 1 H), 8.19 (s, 1 H), 7.95 (d, J=8.40 Hz, 1 H), 7.34 (dd, J=8.40, 1.60 Hz, 1 H), 6.67 (s, 1 H), 6.34 (s, 2 H).
Step e. A solution of 3-aminoisoquinolinecarbonitrile (0.56 g, 3.31 mmol) in concentrated HCl (3.2 ml) was stirred 0°C for 15 min. NaNOz (0.22 g, 3.31 mmol) was added portion wise to the reaction mixture at 0°C and stirred for 30 min. The resulting reaction mixture was poured into ice cold water (50 ml) and basified with saturated aqueous solution of NaHC03. The resulting e was extracted with EtOAc (3 x 60 ml). The ed organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (8% EtOAc in hexane) yielding 3-chloroisoquinolinecarbonitrile (0.40 g, 2.11 mmol). LCMS: Method C, 2.15 min, MS: ES+ 18904, 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.39 (s, 1 H), 8.63 (s, 1 H), 8.39 (d, J=8.40 Hz, 1 H), 8.17 (s, 1 H), 8.02 (dd, J=8.80, 1.60 Hz, 1 H).
Step f. To a solution of 3-chloroisoquinolinecarbonitrile (0.25 g, 1.33 mmol) and tert-butyl 3-(1- aminoethyl)pyrrolidinecarboxylate (0.42 g, 1.99 mmol) in toluene (5 ml) was added t-BuOK (0.29 g, 2.66 mmol) at It. The reaction mixture was degassed for 15 min before addition of Pd2(dba)3 (0.12 g, 0.13 mmol) and Ruphos (0.06 g, 0.13 mmol) at rt. The reaction mixture was heated at 100°C for 16 h. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine solution (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was d by column chromatography (18% EtOAc in hexane) yielding tert-butyl 3-(1-((6-cyanoisoquinolin yl)amino)ethyl)pyrrolidinecarboxylate (0.135 g, 0.36 mmol). LCMS: Method C, 2.58 min, MS: ES+ 367.53.
Steps g, h. The title compound was synthesised from the intermediate above using a procedure r to that bed for Example 9, steps c, d to provide (0.071 g, 0.24 mmol). LCMS: Method A, 4.28 min, MS: ES+ 292.17, 1H NMR (400 MHz, 6) 5 ppm 8.98 (d, J=2.40 Hz, 1 H), 8.16 (s, 1 H), 7.96 (dd, J=8.40, 2.80 Hz, 1 H), 7.32 - 7.36 (m, 1 H), 6.85 (d, J=8.80 Hz, 1 H), 6.71 (s, 1 H), 3.95 - 3.97 (m, 1 H), 3.36 - 3.49 (m, 3 H), 3.14 - 3.16 (m, 1 H), 2.34 - 2.49 (m, 1 H), 1.97 - 1.99 (m, 1 H), 1.67 - 1.69 (m, 1 H), 1.15 (m, 3 H).
Example 52 3-((Benzo[djthiazol-Z-ylamino)(cyan0)methyUpyrrolidine-I-carb0nitrile HKCN-{jf— _, QiHLCN—{D‘e _, QiHLCNH _. QfiHLCNéNo a H b H c H Step a. A mixture of 2-aminobenzothiazole (0.2 g, 1.33 mmol), 1-Boc-pyrrolidinecarboxaldehyde (0.53 g, 2.67 mmol) and NaZSO4 (1.0 g) in MeOH (15 ml) was stirred at rt for 24 h. Acetic acid (0.5 ml) was added to the reaction mixture and stirred at rt for an additional 24 h. The reaction mixture was filtered and excess of MeOH was distilled out. The ed residue was dissolved in THF (5 ml) and lithium perchlorate (0.028 g, 0.267 mmol) was added at It. Trimethylsilyl cyanide (0.263 g, 2.67 mmol) was added to reaction e at 0°C. The reaction e was stirred at rt for 5 h. Additional trimethylsilyl cyanide (0.16 g, 1.60 mmol) and phenol (0.15 g, 1.60 mmol) was added to the reaction mixture and heated to reflux for 16 h. The resulting reaction mixture was poured into saturated NaHC03 on (50 ml) and extracted with EtOAc (3 X 15 ml). The combined organic phase was washed with water (20 ml). The organic phase was separated, dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (20% EtOAc in hexane) yielding utyl 3-((benzo[d]thiazolylamino)(cyano)methyl)pyrrolidine- 1-carboxylate (0.640 g, quantitative). MS: ES+ 359.25.
Step b. To a stirred solution of utyl 3-((benzo[d]thiazolylamino)(cyano)methyl)pyrrolidine carboxylate (0.32 g, 0.894 mmol) in DCM (10 ml) was added TFA (0.68ml) at 0°C. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was concentrated under d pressure. The resulting residue was azeotropically led using DCM (10 ml) yielding 2- (benzo[d]thiazolylamino)(pyrrolidinyl)acetonitrile TFA salt (0.657 g, quantitative). This material was used directly for the next step without further purification. LCMS: Method C, 1.57 min, 1.66 min, MS: ES+ 259.36.
Step c. To a solution of 2-(benzo[d]thiazolylamino)(pyrrolidin-3 -yl)acetonitrile TFA salt (0.65 g, 1.74 mmol) and K2C03 (0.48 g, 3.49 mmol) in THF (10 ml) was added cyanogen e (0.28 g, 2.62 mmol) at -78°C. Five drops of TEA were added to the reaction mixture at -78°C to pH 6. The reaction mixture was stirred at -78°C. The resulting reaction mixture was poured into water (20 ml) and extracted with EtOAc (3 X 15 ml). The combined c phase was dried over , d and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC [mobile phase: (A) 20mM Ammonium acetate in water (B) MeCN, column: X Select Phenyl Hexyl 250x19mm, 5 um, flow rate: 16 ml/min] yielding 3-((benzo[d]thiazolylamino)- (cyano)methyl)pyrrolidinecarbonitrile (0.016 g, 0.056 mmol). LCMS: Method G, 22.80 min, 22.97 min, MS: ES+ 28395, 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.84 (s, 1 H), 7.79 (d, J=8.0 Hz, 1 H), 7.53 (dd, J=2.8 Hz, 8.0 Hz, 1 H), 7.31 (t, J: 8 Hz, 1 H), 7.14 (t, J=7.6 Hz, 1 H), 5.06 - 5.18 (m, 1 H), 3.40 - 3.68 (m, 4 H), 2.88 —2.95 (m, 1 H), 2.08 - 2.21 (m, 1 H), 1.76 - 1.94 (m, 1 H).
Example 53 2-((1-(1-Cyan0pyrrolidinyl)ethyDamino)benzo[d]thiazole-6—carbonitrile a b N: 0'9 NsQN N:\QNW _. N:\Q\N _. N _. I s A SAN _ NH2 3 CI H N’JN Step a. To a on of 4-aminobenzonitri1e (1.00 g, 8.47 mmol) in acetic acid (12 ml) was added potassium thiocyanate (1.00 g, 16.9 mmol) at 10°C. The reaction mixture was stirred at rt for 30 min.
A solution of bromine (0.5 m1, 10.16 mmol) in acetic acid (3 ml) was added dropwise to the reaction at It. The reaction mixture was d at rt for 16 h. The resulting solid precipitates were collected by filtration under reduced re, washed with acetic acid (10 m1) and dried under vacuum. The obtained precipitates were suspended in ice cold aqueous solution ofNH4OH (10 m1) and stirred at rt for 30 min. The resulting solid precipitates were collected by filtration under reduced pressure, dried under vacuum yielding 2-aminobenzo[d]thiazolecarbonitri1e (0.70 g, 4.00 mmol). This material was directly used in the next step without filI'thCI‘ purification. LCMS: Method C, 1.62 min, MS: ES+ 176.13.
Step b. To a on of CuCl (0.13 g, 1.02 mmol) in MeCN (4 ml) was added tert butyl nitrite (0.24 g, 2.00 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 min and then treated with 2- aminobenzo[d]thiazolecarbonitrile (0.18 g, 1.02 mmol). The reaction e was heated at 70°C for 1 h. The resulting reaction mixture was poured into water (50 m1) and extracted with EtOAc (3 X 15 ml). The combined organic phase was dried over NaZSO4, filtered and concentrated under reduced pressure. The residue was triturated with n-pentane (2 X 5 m1) yielding 2-chloro-benzo[d]thiazole carbonitrile (0.165 g, 0.84 mmol). This al was directly used in the next step without filrther purification. LCMS: Method C, 2.27 min, MS: ES+ 195, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.70 (s, 1 H), 8.15 (d, J=8.40 Hz, 1 H), 7.98 (d, J=8.40 Hz, 1 H).
Step c-e. The title nd was synthesised from the intermediate above using a procedure r to that described for Example 9, steps b-d. Method A, 3.90 min, MS: ES+ 2981, 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.58 (d, J=6.00 Hz, 1 H), 8.20 (s, 1 H), 7.62 (d, J=8.40 Hz, 1 H), 7.45 (dd, J=8.40, 2.80 Hz, 1 H), 3.99 - 4.02 (m, 1 H), 3.42 - 3.51 (m, 2 H), 3.36 - 3.39 (m, 1 H), 3.13 - 3.20 (m, 1 H), 2.41 - 2.44 (m, 1 H), 1.97 - 1.99 (m, 1 H), 1.65 - 1.73 (m, 1 H), 1.20 (t, J=8.00 Hz, 3 H).
Example 54 (361R, 661$)Ox0(5-phenylthiazolyl)hexahydr0pyrr010[3, 4-c]pyrr01e-2(1H)- carbonim'le H O-‘é— H by C QES 4. QES MW? 30 s N 4. WW,N-EN W 0 0 Step a. To a solution of 2-bromopheny1thiazole (0.2 g, 0.83 mmol) in 1,4-dioxane (6 ml) was added tert-butyl (3aR,6aR)oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxy1ate (0.17 g, 0.75 mmol) at rt. CuI (0.03 g, 0.16 mmol), K3PO4 (0.71 g, 3.34 mmol) and N,N—dimethylethylenediamine (0.01 g, 0.16 mmol) were added to the reaction e at It. The reaction mixture was heated at 100°C for 4 h. The resulting reaction e was cooled to rt and poured into water (50 ml). The resulting mixture was extracted with EtOAc (3 X 20 ml). The organic phase was collected, dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by solvent trituration using n-pentane (2 X 5 ml). The obtained al was dried under high vacuum to yield tert-butyl (3aR,6aS)oxo(5-phenylthiazolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (0.19 g, 0.49 mmol), LCMS: Method C, 2.40 min, MS: ES+ 386.33.
Step b, c. The title compound was synthesised from the intermediate above using a ure similar to that described for Example 9, steps c, d. LCMS: Method A, 4.15 min, MS: ES+ 31093, 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.97 (s, 1 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 4.16 - 4.21 (m, 1 H), 4.01 - 4.04 (m, 1 H), 3.62 - 3.71 (m, 3 H), 3.55 - 3.56 (m, 1 H), 3.44 - 3.48 (m, 1 H), 3.21 - 3.25 (m, 1 H).
Biological Activity of Compounds of the Invention Abbreviations: TAMRA carboxytetramethylrhodamine PCR polymerase chain reaction PBS phosphate buffered saline EDTA nediaminetetraacetic acid Tris 2-amino(hydroxymethy1)-1,3-propanediol NP-40 Nonidet P-40, octylphenoxypolyethoxyethanol BSA bovine serum albumin PNS peripheral nervous system BH3 Bcl-2 gy domain 3 PTEN phosphatase and tensin homologue In vitro USP30 inhibition assay USP30 mical c assay. Reactions were performed in duplicate in black 384 well plates (small volume, Greiner 784076) in a final reaction volume of 21ul. USP30 CD (57-517, # 64 050 Ubiquigent) was diluted in reaction buffer (40 mM Tris, pH 7.5, 0.005% Tween 20, 0.5 mg/ml BSA, 5 mM beta-mercaptoethanol) to the equivalent of 0, 0.005, 0.01, 0.05, 0.1 and 0.5ul/well. Buffer was optimised for optimal temperature, pH, ng agent, salts, time of incubation, and detergent.
Reactions were initiated by the addition of 50 nM of TAMRA labelled peptide linked to ubiquitin via an iso-peptide bond as fluorescence polarisation substrate. Reactions were incubated at room temperature and read every 2 min for 120 min. Readings were performed on a Pherastar Plus (BMG Labtech). )b Excitation 540 nm, 9» Emission 590 nm.
USP30 mical IC50 assay Dilution plates were ed at 21 times the final concentration (2100 uM for a final concentration of 100 uM) in 50% DMSO in a l polypropylene V-bottom plate (Greiner #651201). A typical 8- point dilution series to be 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 uM final. Reactions were performed in duplicate in black 384 well plates (small volume, Greiner 784076) in a final on volume of 21 ul.
Either 1 ul of 50% DMSO or diluted compound was added to the plate. USP30 was diluted in reaction buffer (40 mM Tris, pH 7.5, 0.005% Tween 20, 0.5 mg/ml BSA, 5 mM beta-mercaptoethanol) to the equivalent of 0.05 ul/well and 10 ul of diluted USP30 was added to the compound. Enzyme and compound were incubated for 30 min at room temp. Reactions were initiated by the addition of 50 nM of TAMRA labelled peptide linked to ubiquitin via an iso-peptide bond as cence polarisation substrate. Reactions were read immediately after addition of substrate and following a 2 hr incubation at room temperature. Readings were performed on a Pherastar Plus (BMG Labtech). 1t Excitation 540 nm, 9» Emission 590 nm.
Activity of Exemplary Compounds in USP30 biochemical IC50 assay Ranges: A<0.1pM; 0.1ooowuoo 46 73 [\JO 47 00060000wwwwwwwwoowwooowwwwo> 74 M4—4 48 75 [\J [\J 49 76 [\J U.) 50 77 N.p 51 78 [\J U1 52 79 003WOOUJUJUJ>O>>UJUJOUJUJUJUJUJUJUJOO> [\J C\ 53 [\J \] 54 The claims defining the invention are as s: 1. A compound of formula (I): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R1b, R1c, R1d, R1e each independently represent hydrogen or C1-C6 alkyl; R1a and R1g each ndently represent hydrogen, fluorine, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy; R1f represents en, fluorine, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy, or R1f together with R2 forms a 5-membered heterocyclic ring; R2 represents hydrogen or C1-C6 alkyl, or R2 together with R1f forms a 5-membered heterocyclic ring; X is C(R3)(R4), wherein R3 and R4 each independently represent hydrogen, cyano or C1-C6 alkyl; L represents a covalent bond, -SO-, -SO2-, -C(O)-, -C(O)O-, -CONR5-, -SO2NR5-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C1-C6 alkylene or -C2-C6 alkenylene; A represents a substituted 5 to 10-membered monocyclic, heteroaryl or aryl ring, or an optionally substituted 9 to bered ic, heteroaryl or aryl ring; R5 ents hydrogen or C1-C6 alkyl; wherein ring A, when substituted, is substituted with one to four -Q1-(R6)n, wherein each occurrence of -Q1-(R6)n is the same or different; n is 0 or 1; Q1 represents halogen, cyano, oxo, nitro, -OR7, -SR7, -NR7R8, -CONR7R8, -NR7COR8, - R8R9, -COR7, R7, -NR7C(O)OR8, -C1-C6 alkyl, -C1-C6 alkoxy, a covalent bond, an oxygen atom, a sulphur atom, C1-C6 alkylene or -C2-C6 alkenylene; R6 is a 3 to 10-membered cyclyl, saturated cycloalkyl, aryl or aryl ring; R7, R8 and R9 each independently represent hydrogen, C1-C6 alkyl or C1-C6 alkylene; wherein R6 is ally substituted with one to four substituents, each independently selected from halogen, cyano, oxo, nitro, -OR10, -SR10, -NR10R11, -C1-C6 alkyl and -C1-C6 alkoxy; R10 and R11 each independently represent hydrogen or C1-C6 alkyl; wherein the heterocyclic ring formed by R1f together with R2 is optionally further substituted with oxo; and wherein said C1-C6 alkyl and C1-C6 alkoxy are each independently optionally substituted with one to four substituents, each independently selected from halogen, hydroxyl, thiol, cyano, amino, nitro and 2. The compound according to claim 1, wherein R1b, R1c, R1d, and R1e are each independently hydrogen or C1-C3 alkyl. 3. The compound according to claim 1, wherein R1a and R1g are each independently hydrogen, fluorine or C1-C6 alkyl. 4. The nd according to any one of claims 1 to 3, wherein R1a, R1b, R1c, R1d, R1e, R1f and R1g are each hydrogen.
. The compound according to any one of claims 1 to 4, wherein R2 is hydrogen or . 6. The compound according to claim 1, wherein X is CH2, CHCN or CHMe. 7. The compound according to claim 1, wherein L is a covalent bond, -SO2-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene or –CONR5-, wherein R5 is hydrogen or methyl. 8. The compound according to any one of claims 1 to 7, wherein the ring of A is a 5 or 6-membered heteroaryl or aryl ring, which is substituted with one to four -Q1-(R6)n. 9. The nd according to claim 8, wherein the ring of A is selected from oxazolyl, isoxazolyl, pyrazolyl, lyl, pyridinyl, pyrimidinyl, phenyl, imidazolyl and oxadiazolyl.
. The compound according to any one of claims 1 to 7, n the ring of A is a 9 or 10- membered bicyclic heteroaryl or aryl ring. 11. The compound according to claim 10, wherein the ring of A is selected from quinolinyl, benzothiazolyl, nolinyl, benzomorpholinyl, indazolyl, imidazopyridinyl, quinazolinyl, pyrazolopyridinyl and benzimidazolyl. 12. The compound according to claim 1, wherein when n is 0, Q1 is selected from halogen, cyano, oxo, -CONR7R8, -NR7COR8, -C1-C6 alkyl and -C1-C6 alkoxy, n said alkyl and alkoxy may be optionally substituted with one to four halogen; and when n is 1, Q1 is selected from a covalent bond, an oxygen atom and methylene. 13. The compound according to claim 1, n the ring of R6 is a selected from phenyl, thiazolyl, pyridinyl, pyrrolidinyl pyrazolyl, isoindolyl, isoxazolyl and cyclopropyl. 14. The compound according to claim 1, wherein R6 is substituted with halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy, wherein the alkyl and alkoxy is ally substituted with one or more fluorine.
. A compound according to claim 1 selected from the group ting of: 3-((quinolinylamino)methyl)pyrrolidinecarbonitrile; 3-(((6-fluorobenzo[d]thiazolyl)amino)methyl)pyrrolidinecarbonitrile; 3-((isoquinolinylamino)methyl)pyrrolidinecarbonitrile; 3-(((6-(1H-pyrazolyl)benzo[d]thiazolyl)amino)methyl)pyrrolidinecarbonitrile; (R)(((7-(1H-pyrazolyl)quinazolinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((3-(1,3-dimethyl-1H-pyrazolyl)phenyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-(1,3-dimethyl-1H-pyrazolyl)phenyl)amino)methyl)pyrrolidinecarbonitrile; -(1,3-dimethyl-1H-pyrazolyl)fluorophenyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((1-cyanopyrrolidinyl)methyl)amino)isoquinolinecarbonitrile; 3-(((1-cyanopyrrolidinyl)methyl)amino)-N-methylisoquinolinecarboxamide; cyanopyrrolidinyl)methyl)methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazine carboxamide; N-((1-cyanopyrrolidinyl)methyl)(pyridinyl)benzamide; N-((1-cyanopyrrolidinyl)methyl)(2,4-dichlorobenzyl)-1H-indazolecarboxamide; 1-benzyl-N-((1-cyanopyrrolidinyl)methyl)-1H-indazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)(N-phenylsulfamoyl)benzamide; (E)-N-((1-cyanopyrrolidinyl)methyl)(2-fluoromethoxyphenyl)acrylamide; (S)-N-((1-cyanopyrrolidinyl)methyl)oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinecarboxamide; (R)chloro-N-((1-cyanopyrrolidinyl)methyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)pyrazolo[1,5-a]pyridinecarboxamide; 2-([1,1'-biphenyl]yl)-N-((1-cyanopyrrolidinyl)methyl)-N-methylacetamide; N-((1-cyanopyrrolidinyl)methyl)(1-methyl-1H-pyrazolyl)imidazo[1,2-a]pyridine carboxamide; 1-(3-chlorophenyl)((1-cyanopyrrolidinyl)methyl)urea; 1-((1-cyanopyrrolidinyl)methyl)(2-fluoromethylphenyl)urea; 1-(3-benzylphenyl)((1-cyanopyrrolidinyl)methyl)urea; 1-((1-cyanopyrrolidinyl)methyl)(2,4-dichlorophenyl)urea; 1-((1-cyanopyrrolidinyl)methyl)(4-(trifluoromethyl)phenyl)urea; N-((1-cyanopyrrolidinyl)methyl)-N-methyl(2-methylthiazolyl)benzenesulfonamide; N-((1-cyanopyrrolidinyl)methyl)-N-methyl((5-(trifluoromethyl)pyridin yl)oxy)benzenesulfonamide; 3-(1-((6-(1H-pyrazolyl)benzo[d]thiazolyl)amino)ethyl)pyrrolidinecarbonitrile; 3-(1-(isoquinolinylamino)ethyl)pyrrolidinecarbonitrile; 3-((1-(1-cyanopyrrolidinyl)ethyl)amino)isoquinolinecarbonitrile; 3-((benzo[d]thiazolylamino)(cyano)methyl)pyrrolidinecarbonitrile; (1-cyanopyrrolidinyl)ethyl)amino)benzo[d]thiazolecarbonitrile; (R)-N-((1-cyanopyrrolidinyl)methyl)-1H-benzo[d]imidazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)isoquinolinecarboxamide; (R)chloro-N-((1-cyanopyrrolidinyl)methyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)cyclopropylimidazo[1,2-a]pyridinecarboxamide; a tautomer thereof, or pharmaceutically acceptable salt of said compound or tautomer. 16. A compound according to claim 1 selected from the group consisting of: (R)(((5-phenylthiazolyl)amino)methyl)pyrrolidinecarbonitrile; (S)(((5-phenylthiazolyl)amino)methyl)pyrrolidinecarbonitrile; N-((1-cyanopyrrolidinyl)methyl)phenyloxazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenylisoxazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-pyrazolecarboxamide; cyanopyrrolidinyl)methyl)(o-tolyl)-1H-pyrazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenylthiazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)(2-fluorophenyl)-1H-pyrazolecarboxamide; cyanopyrrolidinyl)methyl)phenyloxazolecarboxamide; yl-N-((1-cyanopyrrolidinyl)methyl)methyl-1H-pyrazolecarboxamide; 3-(1-((6-(5-methylisoxazolyl)benzo[d]thiazolyl)amino)ethyl)pyrrolidinecarbonitrile; (3aR,6aS)oxo(5-phenylthiazolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonitrile; (R)(3-chlorophenyl)-N-((1-cyanopyrrolidinyl)methyl)isoxazolecarboxamide; ((1-cyanopyrrolidinyl)methyl)phenylisoxazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylthiazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylthiazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-pyrazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-imidazolecarboxamide; (R)(2-chlorophenyl)-N-((1-cyanopyrrolidinyl)methyl)isoxazolecarboxamide; (R)(4-chlorophenyl)-N-((1-cyanopyrrolidinyl)methyl)isoxazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-imidazolecarboxamide; (R)(3-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1H-imidazolecarboxamide; (R)(4-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1H-imidazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(2-methoxyphenyl)-1H-imidazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(3-methoxyphenyl)-1H-imidazolecarboxamide; benzyl-N-((1-cyanopyrrolidinyl)methyl)-1H-imidazolecarboxamide; and (R)-N-((1-cyanopyrrolidinyl)methyl)(cyclopropylmethyl)-1H-imidazolecarboxamide; a tautomer thereof, or ceutically acceptable salt of said compound or tautomer. 17. A compound according to claim 1 selected from the group consisting of: (R)(3-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1,3,4-oxadiazolecarboxamide; and (S)(3-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1,3,4-oxadiazolecarboxamide; a tautomer thereof, or ceutically acceptable salt of said compound or tautomer. 18. A compound according to claim 1 selected from the group consisting of: 3-(((3-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((5-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((6-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-phenylpyrimidinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((2-(isoindolinyl)pyridinyl)amino)methyl)pyrrolidinecarbonitrile; (S)(((4-phenylpyrimidinyl)amino)methyl)pyrrolidinecarbonitrile; N-((1-cyanopyrrolidinyl)methyl)(pyrrolidinyl)picolinamide; N-((1-cyanopyrrolidinyl)methyl)(4-fluorophenyl)nicotinamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylpicolinamide; and (R)-N-((1-cyanopyrrolidinyl)methyl)phenylpicolinamide; a tautomer thereof, or pharmaceutically able salt of said compound or tautomer. 19. Use of a compound according to any one of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the treatment of a condition involving mitochondrial dysfunction.
. The use according to claim 19 wherein the condition involving mitochondrial dysfunction is selected from a neurodegenerative disease; le sclerosis, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes me; Leber's hereditary optic neuropathy; cancer; athy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome; Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric diseases, schizophrenia; multiple ase deficiency; mucolipidosis II; mucolipidosis III; mucolipidosis IV; GMl-gangliosidosis; neuronal ceroid-lipofuscinoses; Alpers disease; Barth syndrome; Beta-oxidation defects; carnitine-acyl-carnitine deficiency; carnitine deficiency; ne deficiency syndromes; co-enzyme Q10 deficiency; x I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external lmoplegia syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency; Leigh disease or syndrome; lethal infantile cardiomyopathy; Luft disease; medium-chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and ragged-red fiber syndrome; mitochondrial cytopathy; mitochondrial ive ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastrointestinal disorder and alopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium/short-chain 3-hydroxyacyl-CoA dehydrogenase ency; very long-chain acyl-CoA dehydrogenase deficiency; and age-dependent decline in cognitive function and muscle strength. 21. The use according to claim 20, wherein the neurodegenerative disease is selected from Parkinson’s disease, mer’s disease, amyotrophic l sclerosis, Huntington’s disease, ia, stroke, dementia with Lewy bodies, and frontotemporal dementia; and Parkinson’s disease related to mutations in α-synuclein, parkin, and PINK1, and autosomal recessive le Parkinson’s disease, where parkin is mutated. 22. Use of a compound according to any one of claims 1 to 18, a er f, or a pharmaceutically acceptable salt of said compound or tautomer, in the cture of a medicament for the treatment of cancer linked to USP30 activity. 23. The use ing to claim 22, wherein the cancer is selected from breast, ovarian, prostate, lung, kidney, c, colon, testicular, head and neck, as, brain, melanoma, bone, cancers of tissue organs, cancers of the blood cells, leukaemia, lymphoma, le myeloma, colorectal cancer, nonsmall cell lung carcinoma, cancer where apoptotic pathways are dysregulated, and cancer where proteins of the BCL-2 family are mutated, or over or under expressed. 24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18, a tautomer thereof, or a ceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.
Figure 1 USP30 kinetic assay for high throughput screening of compounds using an isopeptide linked 3 3 ' OHI \‘=—"'_ " ‘- + it 0.005tu ° t + s 0.01m % g a 4 + ‘ 0.05m e 4 1- 200 0.1m + 0.5m 0 20 40 60 80 100 120 Time (mins)

Claims (24)

The claims defining the invention are as follows:
1. A compound of formula (I): (I) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R 1b, R1c, R1d, R1e each independently represent hydrogen or C1-C6 alkyl; R 1a and R1g each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy; R 1f represents hydrogen, fluorine, cyano, hydroxyl, amino, C1-C6 alkyl or C1-C6 alkoxy, or R1f together with R2 forms a 5-membered heterocyclic ring; R 2 represents hydrogen or C1-C6 alkyl, or R2 together with R1f forms a 5-membered heterocyclic ring; X is C(R3 )(R4 ), wherein R3 and R4 each independently represent hydrogen, cyano or C1-C6 alkyl; L represents a covalent bond, -SO-, -SO2-, -C(O)-, -C(O)O-, -CONR5 -, -SO2NR5 -, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C1-C6 alkylene-C(O)-, C1-C6 alkylene or -C2-C6 alkenylene; A represents a substituted 5 to 10-membered monocyclic, heteroaryl or aryl ring, or an optionally substituted 9 to 10-membered bicyclic, heteroaryl or aryl ring; R 5 represents hydrogen or C1-C6 alkyl; wherein ring A, when substituted, is substituted with one to four -Q1 -(R6 )n, wherein each occurrence of -Q1 -(R6 )n is the same or different; n is 0 or 1; 86 Q1 represents halogen, cyano, oxo, nitro, -OR7 , -SR7 , -NR7R 8 , -CONR7R 8 , -NR7COR8 , - NR7CONR8R 9 , -COR7 , -C(O)OR7 , -NR7C(O)OR8 , -C1-C6 alkyl, -C1-C6 alkoxy, a covalent bond, an oxygen atom, a sulphur atom, C1-C6 alkylene or -C2-C6 alkenylene; R 6 is a 3 to 10-membered heterocyclyl, saturated cycloalkyl, heteroaryl or aryl ring; R 7 , R8 and R9 each independently represent hydrogen, C1-C6 alkyl or C1-C6 alkylene; wherein R6 is optionally substituted with one to four substituents, each independently selected from halogen, cyano, oxo, nitro, -OR10 , -SR10 , -NR10R 11 , -C1-C6 alkyl and -C1-C6 alkoxy; R 10 and R 11 each independently represent hydrogen or C1-C6 alkyl; wherein the heterocyclic ring formed by R 1f together with R2 is optionally further substituted with oxo; and wherein said C1-C6 alkyl and C1-C6 alkoxy are each independently optionally substituted with one to four substituents, each independently selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.
2. The compound according to claim 1, wherein R 1b, R1c, R1d, and R 1e are each independently hydrogen or C1-C3 alkyl.
3. The compound according to claim 1, wherein R 1a and R1g are each independently hydrogen, fluorine or C1-C6 alkyl.
4. The compound according to any one of claims 1 to 3, wherein R 1a, R1b, R1c, R1d, R1e, R1f and R1g are each hydrogen.
5. The compound according to any one of claims 1 to 4, wherein R 2 is hydrogen or methyl.
6. The compound according to claim 1, wherein X is CH2, CHCN or CHMe.
7. The compound according to claim 1, wherein L is a covalent bond, -SO2-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene or –CONR5 -, wherein R5 is hydrogen or methyl.
8. The compound according to any one of claims 1 to 7, wherein the ring of A is a 5 or 6-membered heteroaryl or aryl ring, which is substituted with one to four -Q1 -(R6 )n.
9. The compound according to claim 8, wherein the ring of A is selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, phenyl, imidazolyl and oxadiazolyl.
10. The compound according to any one of claims 1 to 7, wherein the ring of A is a 9 or 10- membered bicyclic heteroaryl or aryl ring. 87
11. The compound according to claim 10, wherein the ring of A is selected from quinolinyl, benzothiazolyl, isoquinolinyl, benzomorpholinyl, indazolyl, imidazopyridinyl, quinazolinyl, pyrazolopyridinyl and benzimidazolyl.
12. The compound according to claim 1, wherein when n is 0, Q1 is selected from halogen, cyano, oxo, -CONR7R 8 , -NR7COR8 , -C1-C6 alkyl and -C1-C6 alkoxy, wherein said alkyl and alkoxy may be optionally substituted with one to four halogen; and when n is 1, Q1 is selected from a covalent bond, an oxygen atom and methylene.
13. The compound according to claim 1, wherein the ring of R 6 is a selected from phenyl, thiazolyl, pyridinyl, pyrrolidinyl pyrazolyl, isoindolyl, isoxazolyl and cyclopropyl.
14. The compound according to claim 1, wherein R6 is substituted with halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy, wherein the alkyl and alkoxy is optionally substituted with one or more fluorine.
15. A compound according to claim 1 selected from the group consisting of: 3-((quinolinylamino)methyl)pyrrolidinecarbonitrile; 3-(((6-fluorobenzo[d]thiazolyl)amino)methyl)pyrrolidinecarbonitrile; 3-((isoquinolinylamino)methyl)pyrrolidinecarbonitrile; 3-(((6-(1H-pyrazolyl)benzo[d]thiazolyl)amino)methyl)pyrrolidinecarbonitrile; (R)(((7-(1H-pyrazolyl)quinazolinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((3-(1,3-dimethyl-1H-pyrazolyl)phenyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-(1,3-dimethyl-1H-pyrazolyl)phenyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-(1,3-dimethyl-1H-pyrazolyl)fluorophenyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((1-cyanopyrrolidinyl)methyl)amino)isoquinolinecarbonitrile; 3-(((1-cyanopyrrolidinyl)methyl)amino)-N-methylisoquinolinecarboxamide; N-((1-cyanopyrrolidinyl)methyl)methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazine carboxamide; N-((1-cyanopyrrolidinyl)methyl)(pyridinyl)benzamide; N-((1-cyanopyrrolidinyl)methyl)(2,4-dichlorobenzyl)-1H-indazolecarboxamide; 1-benzyl-N-((1-cyanopyrrolidinyl)methyl)-1H-indazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)(N-phenylsulfamoyl)benzamide; (E)-N-((1-cyanopyrrolidinyl)methyl)(2-fluoromethoxyphenyl)acrylamide; (S)-N-((1-cyanopyrrolidinyl)methyl)oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinecarboxamide; (R)chloro-N-((1-cyanopyrrolidinyl)methyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)pyrazolo[1,5-a]pyridinecarboxamide; 2-([1,1'-biphenyl]yl)-N-((1-cyanopyrrolidinyl)methyl)-N-methylacetamide; 88 N-((1-cyanopyrrolidinyl)methyl)(1-methyl-1H-pyrazolyl)imidazo[1,2-a]pyridine carboxamide; 1-(3-chlorophenyl)((1-cyanopyrrolidinyl)methyl)urea; 1-((1-cyanopyrrolidinyl)methyl)(2-fluoromethylphenyl)urea; 1-(3-benzylphenyl)((1-cyanopyrrolidinyl)methyl)urea; 1-((1-cyanopyrrolidinyl)methyl)(2,4-dichlorophenyl)urea; 1-((1-cyanopyrrolidinyl)methyl)(4-(trifluoromethyl)phenyl)urea; N-((1-cyanopyrrolidinyl)methyl)-N-methyl(2-methylthiazolyl)benzenesulfonamide; N-((1-cyanopyrrolidinyl)methyl)-N-methyl((5-(trifluoromethyl)pyridin yl)oxy)benzenesulfonamide; 3-(1-((6-(1H-pyrazolyl)benzo[d]thiazolyl)amino)ethyl)pyrrolidinecarbonitrile; 3-(1-(isoquinolinylamino)ethyl)pyrrolidinecarbonitrile; 3-((1-(1-cyanopyrrolidinyl)ethyl)amino)isoquinolinecarbonitrile; 3-((benzo[d]thiazolylamino)(cyano)methyl)pyrrolidinecarbonitrile; 2-((1-(1-cyanopyrrolidinyl)ethyl)amino)benzo[d]thiazolecarbonitrile; (R)-N-((1-cyanopyrrolidinyl)methyl)-1H-benzo[d]imidazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)isoquinolinecarboxamide; (R)chloro-N-((1-cyanopyrrolidinyl)methyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxamide; and (R)-N-((1-cyanopyrrolidinyl)methyl)cyclopropylimidazo[1,2-a]pyridinecarboxamide; a tautomer thereof, or pharmaceutically acceptable salt of said compound or tautomer.
16. A compound according to claim 1 selected from the group consisting of: (R)(((5-phenylthiazolyl)amino)methyl)pyrrolidinecarbonitrile; (S)(((5-phenylthiazolyl)amino)methyl)pyrrolidinecarbonitrile; N-((1-cyanopyrrolidinyl)methyl)phenyloxazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenylisoxazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-pyrazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)(o-tolyl)-1H-pyrazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenylthiazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)(2-fluorophenyl)-1H-pyrazolecarboxamide; N-((1-cyanopyrrolidinyl)methyl)phenyloxazolecarboxamide; 1-benzyl-N-((1-cyanopyrrolidinyl)methyl)methyl-1H-pyrazolecarboxamide; 3-(1-((6-(5-methylisoxazolyl)benzo[d]thiazolyl)amino)ethyl)pyrrolidinecarbonitrile; (3aR,6aS)oxo(5-phenylthiazolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonitrile; 89 (R)(3-chlorophenyl)-N-((1-cyanopyrrolidinyl)methyl)isoxazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylisoxazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylthiazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylthiazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-pyrazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-imidazolecarboxamide; (R)(2-chlorophenyl)-N-((1-cyanopyrrolidinyl)methyl)isoxazolecarboxamide; (R)(4-chlorophenyl)-N-((1-cyanopyrrolidinyl)methyl)isoxazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenyl-1H-imidazolecarboxamide; (R)(3-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1H-imidazolecarboxamide; (R)(4-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1H-imidazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(2-methoxyphenyl)-1H-imidazolecarboxamide; (R)-N-((1-cyanopyrrolidinyl)methyl)(3-methoxyphenyl)-1H-imidazolecarboxamide; (R)benzyl-N-((1-cyanopyrrolidinyl)methyl)-1H-imidazolecarboxamide; and (R)-N-((1-cyanopyrrolidinyl)methyl)(cyclopropylmethyl)-1H-imidazolecarboxamide; a tautomer thereof, or pharmaceutically acceptable salt of said compound or tautomer.
17. A compound according to claim 1 selected from the group consisting of: (R)(3-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1,3,4-oxadiazolecarboxamide; and (S)(3-cyanophenyl)-N-((1-cyanopyrrolidinyl)methyl)-1,3,4-oxadiazolecarboxamide; a tautomer thereof, or pharmaceutically acceptable salt of said compound or tautomer.
18. A compound according to claim 1 selected from the group consisting of: 3-(((3-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((5-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((6-phenylpyridinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((4-phenylpyrimidinyl)amino)methyl)pyrrolidinecarbonitrile; 3-(((2-(isoindolinyl)pyridinyl)amino)methyl)pyrrolidinecarbonitrile; (S)(((4-phenylpyrimidinyl)amino)methyl)pyrrolidinecarbonitrile; N-((1-cyanopyrrolidinyl)methyl)(pyrrolidinyl)picolinamide; N-((1-cyanopyrrolidinyl)methyl)(4-fluorophenyl)nicotinamide; (R)-N-((1-cyanopyrrolidinyl)methyl)phenylpicolinamide; and (R)-N-((1-cyanopyrrolidinyl)methyl)phenylpicolinamide; a tautomer thereof, or pharmaceutically acceptable salt of said compound or tautomer. 90
19. Use of a compound according to any one of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the treatment of a condition involving mitochondrial dysfunction.
20. The use according to claim 19 wherein the condition involving mitochondrial dysfunction is selected from a neurodegenerative disease; multiple sclerosis, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome; Leber's hereditary optic neuropathy; cancer; neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome; Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric diseases, schizophrenia; multiple sulfatase deficiency; mucolipidosis II; mucolipidosis III; mucolipidosis IV; GMl-gangliosidosis; neuronal ceroid-lipofuscinoses; Alpers disease; Barth syndrome; Beta-oxidation defects; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndromes; co-enzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency; Leigh disease or syndrome; lethal infantile cardiomyopathy; Luft disease; medium-chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and ragged-red fiber syndrome; mitochondrial cytopathy; mitochondrial recessive ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastrointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; very long-chain acyl-CoA dehydrogenase deficiency; and age-dependent decline in cognitive function and muscle strength.
21. The use according to claim 20, wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, ischemia, stroke, dementia with Lewy bodies, and frontotemporal dementia; and Parkinson’s disease related to mutations in α-synuclein, parkin, and PINK1, and autosomal recessive juvenile Parkinson’s disease, where parkin is mutated.
22. Use of a compound according to any one of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the treatment of cancer linked to USP30 activity.
23. The use according to claim 22, wherein the cancer is selected from breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone, cancers of tissue organs, cancers of the blood cells, leukaemia, lymphoma, multiple myeloma, colorectal cancer, nonsmall cell lung carcinoma, cancer where apoptotic pathways are dysregulated, and cancer where proteins of the BCL-2 family are mutated, or over or under expressed. 91
24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.
NZ741411A 2015-12-17 2016-12-16 Cyanopyrrolidines with activity as inhibitors of deubiquitylating enzymes (DUBs) NZ741411B2 (en)

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GBGB1522267.2A GB201522267D0 (en) 2015-12-17 2015-12-17 Novel compounds
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PCT/GB2016/053971 WO2017103614A1 (en) 2015-12-17 2016-12-16 Novel Compounds

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NZ741411B2 true NZ741411B2 (en) 2022-06-28

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