1-Cyanopyrrolidine Compounds as Inhibitors of USP30

专利摘要:

公开号:ES2864950T9
申请号:ES16713043T
申请日:2016-03-24
公开日:2021-11-18
发明作者:Alison Jones；Mark KEMP；Martin Stockley；Karl Gibson；Gavin WHITLOCK
申请人:Mission Therapeutics Ltd；
IPC主号:

专利说明:

[0002] 1-Cyanopyrrolidine Compounds as Inhibitors of USP30
[0004] The present invention relates to new compounds and methods for the manufacture of desubiquitinating enzyme inhibitors (DUB). In particular, the invention relates to the inhibition of C-terminal ubiquitin hydrolase 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.
[0006] Background of the invention
[0008] The listing or discussion of an apparently previously published document in this specification should not necessarily be taken as an acknowledgment that the document is part of the state of the art or is common general knowledge.
[0010] Ubiquitin is a small protein consisting of 76 amino acids that is important for the regulation of protein function in the cell. Ubiquitination and deubiquitination are enzymatically mediated procedures whereby ubiquitin is covalently bound to or cleaved from a target protein by deubiquitinating enzymes (DUB), of which there are approximately 95 DUB in human cells, divided into subfamilies based on sequence homology . The USP family is characterized by its common Cys and His boxes that contain Cys and His residues critical for its DUB activities. The processes of ubiquitination and desubiquitination have been implicated in the regulation of many cellular functions, including cell cycle progression, apoptosis, modification of cell surface receptors, regulation of DNA transcription, and DNA repair. Therefore, the ubiquitin system has been implicated in the pathogenesis of numerous disease states including inflammation, viral infection, metabolic dysfunction, CNS disorders, and oncogenesis (Clague et al., Physiol Rev 93: 1289-1315, 2013).
[0012] Ubiquitin is a master regulator of mitochondrial dynamics. Mitochondria are dynamic organelles whose biogenesis, fusion, and fission events are regulated by post-translational regulation through the ubiquitination of many key factors such as mitofusins. While ubiquitin ligases such as parkin are known to ubiquitinate a number of mitochondrial proteins, until recently, deubiquitinating enzymes remained elusive. USP30 is a 517 amino acid protein found in the mitochondrial outer membrane (Nakamura et al., Mol Biol 19: 1903-11, 2008). It is the only desubiquitinating enzyme that carries a mitochondrial targeting signal and has been shown to desubiquitin several mitochondrial proteins. USP30 has been shown to oppose parkin-mediated mitophagy and that reduction of USP30 activity can rescue parkin-mediated defects in mitophagy (Bingol et al., Nature 510: 370-5, 2014).
[0014] Mitochondrial dysfunction can be defined as a decrease in mitochondrial content (mitophagy or mitochondrial biogenesis), as a decrease in mitochondrial activity and oxidative phosphorylation, but also as a modulation of the generation of reactive oxygen species (ROS). Hence a role for mitochondrial dysfunctions in a host of aging procedures and pathologies including, but not limited to, neurodegenerative diseases (eg, Parkinson's disease (PD), Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), muscular sclerosis), cancer, diabetes, metabolic disorders, cardiovascular diseases, psychiatric diseases (eg, schizophrenia), and osteoarthritis.
[0016] For example, Parkinson's disease affects around 10 million people worldwide (Parkinson's Disease Foundation) and is characterized by the loss of dopaminergic neurons in the substantia nigra. The exact mechanisms underlying PD are unclear; however, mitochondrial dysfunction is increasingly appreciated as a key determinant of neuronal dopaminergic susceptibility in PD and is a feature of familial and sporadic disease, as well as toxin-induced parkinsonism. Parkin is one of several proteins that have been linked to early-onset PD. While the majority of PD cases are related to defects in alpha-synuclein, 10% of Parkinson's cases are related to specific genetic defects, one of which is in ubiquitin E3 ligase parkin. Parkin and putative kinase 1 induced by the PTEN protein kinase (PINK1) collaborate to ubiquitinate the mitochondrial membrane proteins of damaged mitochondria, resulting in mitophagy. Dysregulation of mitophagy results in increased oxidative stress, which has been described as a feature of PD. Therefore, inhibition of USP30 could be a potential strategy for the treatment of PD. For example, PD patients with parkin mutations leading to reduced activity could be compensated therapeutically by inhibiting USP30.
[0018] Depletion of USP30 has been reported to improve mitophagic clearance from mitochondria and also enhance parkin-induced cell death (Liang et al., EMBO Reports 2015 DOI : 10,15252 / embr.201439820). USP30 has also been shown to regulate BAX / BAK-dependent apoptosis independently of parkin overexpression. Depletion of USP30 sensitizes cancer cells to BH-3 mimetics such as ABT-737, without the need for overexpression of parkin. Thus, an antiapoptotic role for USP30 has been demonstrated, and thus USP30 is a potential target for anticancer therapy.
[0020] To date, there have been no reports of DUB inhibitors successfully entering the clinic. Therefore, There is a need for compounds and pharmaceutical compositions to inhibit DUBs such as USP30 for the treatment of indications in which DUB activity is observed, including, but not limited to, conditions involving mitochondrial dysfunction and cancer.
[0021] Lainé et al., Med Chem Lett. 2011, 2 (2), 142-7 describe the compound N - [(3R) -1-cyano-3-pyrrolidinyl] -4-fluorobenzamide as an inhibitor of cathepsin C. Document WO2001 / 077073 describes the compounds N- ( 1-cyano-3-pyrrolidinyl) - [1,1'-biphenyl] -4-carboxamide and N- (1-cyano-3-piperidinyl) - [1,1'-biphenyl] -4-carboxamide as cathepsin inhibitors . WO2009 / 129371 describes the compounds N - [(3R) -1-cyano-3-pyrrolidinyl] -3 - ({[(3R) -1-cyano-3-pyrrolidinyl] amino} sulfonyl) benzamide and N- [ (3R) -1-cyano-3-pyrrolidinyl] -3 - ([(3R) -3-pyrrolidinylamino] sulfonyl) -benzamide as Cathepsin C inhibitors. WO2016 / 021629 describes compound 1 - ((3S, 4R ) -1-cyano-4- (3,4-difluorophenyl) pyrrolidin-3-yl) -3- (1 ', 4-dimethyl-1-phenyl-1H, 1'H- [3,4'-bipyrazole] -5-yl) ureayl) urea as a TrkA inhibitor. These compounds can be rejected by the appended claims.
[0022] Falgueyret et al., J. Med. Chem. 2001,44, 94-104, and PCT Application WO 01/77073 refer to cyanopyrrolidines as inhibitors of cathepsins K and L, with potential utility in the treatment of osteoporosis and other conditions related to bone resorption. US 2012/077806 refers to a series of acrylamides as potential inhibitors of DUB USP9x.
[0023] Summary of the invention
[0024] According to a first aspect of the invention there is provided:
[0025] (i) a compound of formula (II)
[0029] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: m is 0 or 1;
[0030] when m is 1, Z is -C (R ⁶ ) (R ⁷ ) -;
[0031] R ² represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
[0032] R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0033] R ¹ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0034] R ⁹ represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R ¹⁰ ;
[0035] R ¹⁰ represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R ⁹ , or forms a monocyclic ring with R ¹¹ ;
[0036] Y represents a covalent bond, -C ^{0 -C 3} alkylene -N (R ¹¹ ) -C0-C3 alkylene or C1-C3 alkylene;
[0037] R ¹¹ represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R ¹⁰ ;
[0038] R ¹² represents a 3- to 14-membered monocyclic, optionally substituted bicyclic or optionally substituted tricyclic 3- to 14-membered heteroaryl, heterocyclyl or cycloalkyl ring;
[0039] where R ¹² , when substituted, is substituted with one or more of -Q ¹ - (R ¹³ ) p, where:
[0040] p is 0 or 1;
[0041] Q ¹ represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (Co-C ³ ) -NR ¹⁴ -, -alkylene (Co-C3) -NR ¹⁴ R ¹⁵ , -alkylene (C0-C3 ) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, an oxygen atom, -alkylene (C ⁰ -C ³ ) -CO-, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C0-C3) -NR ¹⁴ SO2NR ¹⁵ R ¹⁶ , -alkylene (C0-C3) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO ² R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ - C ³ ) -C (O) R ¹⁴ and (C1-C6) alkylene -NR ¹⁴ SO2R ¹⁵ , NO2, C1-C6 alkylene, -C2-C6 alkenylene, or an optionally substituted -C1-C6 alkyl group;
[0042] q is 0, 1 or 2;
[0043] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group;
[0044] when p is 1, R ¹³ represents a heteroaryl, heterocyclyl, 4 to 10 membered aryl or 3 to 8 membered cycloalkyl ring; wherein R ¹³ may be optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-hydroxyalkyl C6, oxo, cyano, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , - Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ , -Q ² -SO2NR ¹⁷ R ¹⁸ , -Q ² -NR ¹⁷ SO2R ¹⁸ , heterocyclyl, cycloalkyl, heteroaryl, and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH ³ ) ² , and CO2CH2CH3;
[0045] Q ² represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; R ¹⁶ , R ¹⁷ , R ¹⁸ each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl; Y
[0046] wherein the optional alkyl substituents of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and Q ¹ , which may be the same or different, are selected from C1 alkoxy -C3, halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5;
[0047] (ii) a compound of formula (II)
[0051] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: m is 0 or 1;
[0052] when m is 1, Z is -C (R ⁶ ) (R ⁷ ) -;
[0053] R ² represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
[0054] R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0055] R ¹ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0056] R ⁹ represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R ¹⁰ ;
[0057] R ¹⁰ represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R ⁹ , or forms a monocyclic ring with R ¹¹ ;
[0058] Y represents a covalent bond, -alkylene (Co-C ³ ) -N (R ¹¹ ) -C0-C3 alkylene or C1-C3 alkylene;
[0059] R ¹¹ represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R ¹⁰ ;
[0060] R ¹² represents a 3- to 14-membered monocyclic substituted, optionally substituted bicyclic or optionally substituted tricyclic aryl ring;
[0061] where R ¹² , when substituted, is substituted with one or more of -Q ¹ - (R ¹³ ) p, where:
[0062] p is 0 or 1;
[0063] Q ¹ represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ -, -alkylene (C0-C3) -NR ¹⁴ R ¹⁵ , -alkylene (C0- C3) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, an oxygen atom, -alkylene (C ⁰ -C ³ ) -CO-, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -C1-C6 alkoxy, C1-C6 haloalkoxy , C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ , -alkylene (C0-C3) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO2R ¹⁵ , -alkylene (C0-C3) -SO2NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -C (O) R ¹⁴ and alkylene (C1-C6 ) -NR ¹⁴ SO2R ¹⁵ , NO2, C1-C6 alkylene, -C2-C6 alkenylene, or an optionally substituted -C1-C6 alkyl group;
[0064] q is 0, 1 or 2;
[0065] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group; when p is 1, R ¹³ represents a heteroaryl, 4 to 10 membered heterocyclyl or 3 to 8 membered cycloalkyl ring; wherein R ¹³ may be optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-hydroxyalkyl C6, oxo, cyano, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , - Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ , -Q ² -SO2NR ¹⁷ R ¹⁸ , -Q ² -NR ¹⁷ SO2R ¹⁸ , heterocyclyl, cycloalkyl, heteroaryl, and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH ³ , CONH2, NHC (O) CH ( CH ³ ) ² , and CO ² CH ² CH ³ ;
[0066] Q ² represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; R ¹⁶ , R ¹⁷ , R ¹⁸ each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl;
[0067] wherein the optional alkyl substituents of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and Q ¹ , which may be the same or different, are selected from C1 alkoxy -C3, halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5; and where the compound does not have the formula:
[0071] Y
[0072] (iii) a compound of formula (II)
[0076] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: m is 0 or 1;
[0077] when m is 1, Z is -C (R ⁶ ) (R ⁷ ) -;
[0078] R ² represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
[0079] R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0080] R ¹ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0081] R ⁹ represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R ¹⁰ ;
[0082] R ¹⁰ represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R ⁹ , or forms a monocyclic ring with R ¹¹ ;
[0083] Y represents a covalent bond, -C ^{0 -C 3} alkylene -N (R ¹¹ ) -C0-C3 alkylene or C1-C3 alkylene;
[0084] R ¹¹ represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R ¹⁰ ;
[0085] R ¹² represents a 3- to 14-membered monocyclic, bicyclic or tricyclic aryl ring;
[0086] where R ¹² is substituted with one or more of -Q ¹ - (R ¹³ ) p, where:
[0087] p is 1;
[0088] Q ¹ represents cyano, oxo, hydroxyl, a covalent bond, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ R ¹⁵ , -alkylene (C0-C3) - CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, an oxygen atom, -alkylene (C0-C ³ ) -CO -, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C0-C3) -SO2NR ¹⁴ , -alkylene (C0-C3) -SO2NR ¹⁴ R ¹⁵ , -alkoxy C1-C6, haloalkoxy C1-C ⁶ , C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ , -alkylene (C ⁰ -C ³ ) - NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO2R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -C ( O) R ¹⁴ and (C1-C6) alkylene -NR ¹⁴ SO2R ¹⁵ , NO2, C1-C6 alkylene, -C2-C6 alkenylene, or an optionally substituted -C1-C6 alkyl group;
[0089] q is 0, 1 or 2;
[0090] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group;
[0091] when p is 1, R ¹³ represents a 4 to 10 membered aryl ring; wherein R ¹³ is substituted with one or more substituents selected from C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO ² R ¹⁸ , -Q ² -SO ² R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO ² R ¹⁷ , -Q ² -SO ² NR ¹⁷ R ¹⁸ , -Q ² -NR ¹⁷ SO ² R ¹⁸ , heterocyclyl, cycloalkyl, heteroaryl, and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH ³ ) ² , and CO2CH2CH3
[0092] Q ² represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; R ¹⁶ , R ¹⁷ , R ¹⁸ each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl; Y
[0094] wherein the optional alkyl substituents of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and Q ¹ , which may be the same or different, are selected from C1 alkoxy -C3, halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5.
[0096] Brief description of the figures
[0098] Figure 1 is a graph showing the proteolytic activity of USP30 measured using a fluorescence polarization assay. Several volumes of purified USP30 were incubated as indicated with a TAMRA-labeled peptide bound to ubiquitin via an isopeptide linkage.
[0100] Detailed description of the invention
[0102] The following definitions and explanations correspond to terms that are used throughout this specification, including both the specification and the claims. Reference to compounds as described herein (eg, a compound of Formula I), includes reference to Formula I, Formula II, and Formula III, including any of their subgeneric embodiments.
[0104] When any group of the compounds of formula (I) has been referred to as optionally substituted, this group may be substituted as described in the claims, or unsubstituted. The substitution can be with one or more of the specified substituents which can be the same or different. It will be appreciated that the number and nature of the substituents will be selected to avoid any sterically undesirable combinations.
[0105] In the context of the present specification, unless otherwise indicated, an alkyl, alkenyl or alkynyl substituent group or an alkyl or alkenyl radical in a substituent group can be linear or branched. The alkyl and alkenyl chains can also include intermediate heteroatoms such as oxygen.
[0107] Cx-Cy alkyl refers to a saturated aliphatic hydrocarbon group having x and carbon atoms that can be linear or branched. For example, C1-C6 alkyl contains 1 to 6 carbon atoms. "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 include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl- 2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
[0109] A CX-Cy alkylene group or radical may be straight or branched and refers to a divalent hydrocarbon group having one hydrogen atom less than CX-Cy alkyl as defined above. Examples of C1-C6 alkylene groups include methylene, ethylene, n-propylene, n-butylene, methylmethylene, and dimethylmethylene.
[0111] C2-C6 alkenyl refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-hexenyl, 2-methyl-1-propenyl, 1,2-butadienyl, 1,3-pentadienyl, 1,4- pentadienyl and 1-hexadienyl.
[0113] C2-C6 alkynyl refers to a straight 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, 1-butynyl, 2-butynyl, and 1-hexinyl.
[0115] C ¹ -C ⁶ alkoxy refers to a group or part of a group having an alkyl group -O-CX-Cy as defined above for CX-Cy alkyl. Examples of C1-C6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and hexoxy.
[0117] ^C1 - ^C6 haloalkyl and haloalkoxy ^C1 - ^C6 alkyl refer to a group CX-C as defined above wherein at least one the hydrogen atom is replaced by a halogen atom. Examples of C1-C6 haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.
[0119] C ¹ -C ⁶ hydroxyalkyl refers to a CX-Cy alkyl group as defined above wherein at least one hydrogen atom is replaced by a hydroxy group (-OH). Examples of hydroxyC 1-6 alkyl groups include hydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, and hydroxyisopropyl.
[0121] The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine atoms.
[0123] The term "oxo" means = O.
[0125] For the avoidance of doubt, it will be understood that a 4 to 10 membered heteroaryl, heterocyclyl or aryl ring, or a 3 to 8 membered cycloalkyl ring as defined by R ² , R ⁹ , R ¹¹ or R ¹³ or a ring of 3-14 membered heteroaryl, heterocyclyl, cycloalkyl or aryl as defined by R ¹² does not include any unstable ring structure or, in the case of heteroaryl and heterocyclic ring systems, no OO, OS or SS bonds. Ring systems they can be monocyclic, bicyclic, or tricyclic where the definition allows. Bicyclic and tricyclic ring systems include bridged, condensed and spiro ring systems, particularly fused ring systems. A substituent, if present, can be attached to any suitable ring atom which can be a carbon atom or, in the case of heteroaryl and heterocyclic ring systems, a hetero atom. Substitution on a phenyl ring can include a ring atom change in the substitution position from carbon to nitrogen, resulting in a pyridine ring.
[0127] "Cx-Cy cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group of xy carbon atoms. For example, "C3-C8 cycloalkyl" refers to a hydrocarbon ring containing 3 to 8 carbon atoms. Examples of C3-C8 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
[0129] An "aryl" group / radical refers to any monocyclic or bicyclic hydrocarbon group comprising at least one aromatic group, eg, having up to 10 ring member carbon atoms. Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.
[0131] The "heteroaryl" groups can be monocyclic, bicyclic, or tricyclic. Bicyclic rings can be fused aromatic rings where both rings are aromatic or they can be fused rings where one of the rings is non-aromatic. In the case of R ¹² , the amide nitrogen-attached ring can be an aromatic ring, which can be fused to an additional aromatic or non-aromatic ring. Heteroaryl rings comprise 1, 2, 3 or 4 heteroatoms, in particular 1, 2 or 3 heteroatoms, selected from oxygen, sulfur and nitrogen. When the heteroatom is nitrogen, it can be oxidized. Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, iso, purinyl, furazanyl, imidazolyl, isidazolyl, isozolyl, imidazolyl, isoxazolyl oxadiazolyl, oxazinanilo, tetrazolyl, thiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, pyridazinyl, dihydropyridinyl, benzopyrazolyl, quinoxalinyl, tetrahydropyridoindolyl, benzimidazolyl, pyrrolopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, and imidazopyrazinyl.
[0133] The "heterocyclyl" groups can also be monocyclic or comprise two or more fused rings that can be saturated or partially unsaturated comprising 1, 2, 3 or 4 heteroatoms, in particular 1, 2 or 3 heteroatoms, selected from oxygen, sulfur and nitrogen . Examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofuranyl (eg, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxolanyl, morpholinyl, oxazolidinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (eg, 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, pyridazukinyl, tetrahydropyranyl, quinhydropyranyl, tetrahydropyranyl, quininehydropynyl tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylene sulfoxide, thiazolidinyl, hydantoinyl, benzopyranyl, tetrahydrothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, and dihydroisoquinolinyl.
[0135] "Optionally substituted" applied to any group means that said group may, if desired, be substituted with one or more substituents, which may be the same or different. Examples of suitable substituents for "substituted" and "optionally substituted" radicals include halo, deuterium, C1-C6 alkyl or C1-C3 alkyl, hydroxy, C1-C6 alkoxy or C1-C3 alkoxy, cyano, amino, nitro, or SF5 ( a known mimetic of NO2), aryl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, (C ¹ -C ³ ) alkyl amino, alkenyl (C2-C6) amino, dialkyl (C ¹ -C ³ ) amino, acyl (C ¹ -C ³ ) amino, diacyl (C1-C ³ ) amino, carboxy, (C ¹ -C ³ ) alkoxy carbonyl, carbamoyl, C1-C3 monocarbamoyl, C1-C3 dicarbamoyl or any of the above in which a hydrocarbyl radical is replaced in turn with halo. In groups containing an oxygen atom such as hydroxy and alkoxy, the oxygen atom can be replaced by sulfur to form groups such as thio (SH) and thio-alkyl (S-alkyl). Thus, optional substituents include groups such as S-methyl. In thio-alkyl groups, the sulfur atom can be further oxidized to form a sulfoxide or a sulfone, and therefore optional substituents include groups such as S (O) -alkyl and S (O) 2-alkyl.
[0137] Substituted groups include for example, Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH ³ ) ² , CO2CH2CH3 etc. In the case of aryl groups, the substitutions can be in the form of rings of adjacent carbon atoms on the aryl ring, for example cyclic acetals such as O-CH2-O.
[0139] Optional substituents for any alkyl, alkenyl, alkynyl, alkoxy, alkylene, or alkenylene group described herein may be selected from C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano, amino, amido, nitro, and SF5, wherein the alkoxy can be optionally substituted with halogen. In particular, the optional substituents can be selected from halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5, more specifically fluorine or hydroxyl.
[0141] The terms "treat" or "treating" or "treatment" include prophylaxis and means to improve, alleviate symptoms, eliminate the cause of symptoms, either temporarily or permanently, or to prevent or delay the onset of symptoms. mentioned disorder or condition. The compounds of the invention are useful in the treatment of humans and non-human animals.
[0142] The dose of the compound is that amount effective to prevent the appearance of the symptoms of the disorder or to treat some symptoms of the disorder suffered by the patient. By "effective amount" or "therapeutically effective amount" or "effective dose" is meant the amount sufficient to elicit the desired pharmacological or therapeutic effects, thus producing effective prevention or treatment of the disorder. Prevention of the disorder is manifested by delaying the onset of symptoms of the disorder to a medically significant degree. Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an improvement in the reappearance of the symptoms of the disorder.
[0144] Pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, addition salts (eg, phosphates, nitrates, sulfates, borates, acetates, maleates, citrates, fumarates, succinates, methanesulfonates, benzoates, salicylates, and hydrohalides). , salts derived from organic bases (such as lithium, potassium and sodium), amino acid salts (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine and proline), inorganic bases (such as triethylamine, hydroxide, choline, thiamine and N-N'-diacetylethylenediamine). Other pharmaceutically acceptable salts include ammonium salts, substituted ammonium salts, and aluminum salts. Additional pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of formula (I) or formula (II).
[0146] General methods for the production of salts are well known to those skilled in the art. Such salts can be formed by conventional means, for example, by reacting a free acid or free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in where the salt is insoluble, followed by removal of said solvent, or said medium, using conventional techniques (eg, under vacuum, by lyophilization or by filtration). Salts can also be prepared by exchanging a counter ion of a compound in salt form for another counter ion, for example, using a suitable ion exchange resin.
[0148] When the compounds of the invention exist in different enantiomeric and / or diastereoisomeric forms, the invention relates to these compounds prepared as isomeric mixtures or racemates, whether they are present in an optically pure form or as mixtures with other isomers. Enantiomers differ only in their ability to rotate plane-polarized light in equal amounts in opposite directions and are denoted as (+) / (S) or (-) / (R forms respectively. Individual enantiomers or isomers can be prepared by methods known in the art, such as optical resolution of products or intermediates (eg, chiral chromatographic separation, eg, chiral HPLC or an asymmetric synthesis approach). Similarly, when compounds of the invention exist as forms Alternative tautomers, eg keto / enol, amide / imidic acid, the invention relates to the isolated individual tautomers and to mixtures of the tautomers in all proportions.
[0150] The disclosure includes the compound according to formula (IB):
[0155] or a pharmaceutically acceptable salt thereof, wherein n, X, R1, R2, R3, R8, R9, R10, ^R12 and Y are defined herein for compounds of formula (I).
[0156] Included herein is the compound according to formula (III):
[0160] or a pharmaceutically acceptable salt thereof, where m, Z, R1, R2, R3, R8, R9, R10, R ¹² and Y are defined above for the compounds of formula (II).
[0161] Isotopes
[0162] 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 element. For example, a reference to hydrogen includes within its scope ¹ H, ² H (D), and ³ H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹² C, 13C and 14C and 16O and ¹⁸ O. Examples of isotopes include ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ³⁶ Cl, ¹⁸ F, ¹²³ I, ¹²⁵ I, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, 32P, and ³⁵ S. Similarly, a reference to a particular functional group also includes isotopic variations within its scope. , unless the context 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 group's hydrogen atoms are in the form of a deuterium or tritium isotope, e.g. ex. as in an ethyl group where the five hydrogen atoms are in the isotopic form of deuterium (a perdeuteroethyl group).
[0163] Isotopes can be radioactive or non-radioactive. In one embodiment, the compounds do not contain radioactive isotopes. These compounds are preferred for therapeutic use. In another embodiment, however, the compounds may contain one or more radioisotopes. Compounds containing such radioisotopes can be useful in a diagnostic context.
[0164] Certain isotopically-labeled compounds of formula (I) or formula (II), for example, those incorporating a radioactive isotope, are useful in drug studies and / or substrate tissue distribution. Radioactive isotopes, ie, 3H and 14C are particularly useful for this purpose in view of their ease of incorporation and easy means of detection. Substitution by heavier isotopes, i.e. ² H, may provide certain therapeutic benefits resulting from increased metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and may therefore be preferable in some circumstances. Substitution with positron-emitting isotopes, such as ¹¹ C, ¹⁸ F, 15O, and ¹³ N, may be useful in positron emission topography (PET) studies to examine receptor occupancy. Isotopically-labeled compounds of formula (I) or formula (II) can generally be prepared by conventional mechanisms known to those skilled in the art or by procedures analogous to those described in the accompanying examples and preparations using an appropriate isotopically-labeled reagent in place of the previously used unlabeled reagent.
[0165] Crystalline and amorphous forms
[0166] Compounds of formula (I) or formula (II) may exist in crystalline 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) or formula (II) can be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, infrared spectra, Raman spectra, X-ray powder diffraction. , Differential Scanning Calorimetry, Thermogravimetric Analysis and Solid State Nuclear Magnetic Resonance.
[0167] Accordingly, in further embodiments, the invention provides a compound according to any of the described embodiments in crystalline form. The compound can be ⁵⁰ % to ¹⁰⁰ % crystalline, and more specifically it 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 less ^95% crystalline, or at the least ^98% crystalline, or at the least ^99% crystalline, or at the least ^{9 9 5%} crystalline, or at the least ^{9 9 9%} crystalline, for example ^100% crystalline. Alternatively, the compound can be in amorphous form.
[0168] The invention described herein refers to all crystalline forms, solvates and hydrates of any of the compounds described, regardless of their preparation. To the extent that any of the compounds described herein have acidic or basic centers such as carboxylate or amino groups, all salt forms of such compounds are included herein. In the case of pharmaceutical uses, the salt should be considered to be a pharmaceutically acceptable salt.
[0170] The invention relates to any solvate of the compounds and their salts. Preferred solvates are solvates formed by incorporation into the solid state structure (eg, crystalline structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or a mixture of solvents containing the solvating solvent. Whether or not a solvate has formed in a given case can be determined by subjecting crystals of the compound to analysis using well known and conventional techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
[0172] The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by s Sc I, Inc of West Lafayette, IN, USA. , 1999, ISBN 0-967-06710-3.
[0174] The disclosure includes pharmaceutically functional derivatives of compounds as defined herein, including ester derivatives and / or derivatives that have, or provide, the same biological function and / or activity as any relevant compound of the invention. Thus, for the purposes of this description, the term also includes prodrugs of compounds as defined herein.
[0176] The term "prodrug" of a relevant compound includes any compound that, after oral or parenteral administration, is metabolized in vivo to form that compound in an experimentally detectable amount, and within a predetermined time (eg, within a dosing interval of between 6 and 24 hours (that is, one to four times a day).
[0178] Prodrugs of compounds can be prepared by modifying functional groups present on the compound such that the modifications are cleaved, in vivo when such a prodrug is administered to a mammalian subject. Modifications are typically achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group of a compound is attached to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively.
[0180] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, e.g. ex. in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elsevier, New York-Oxford (1985).
[0182] The compounds of the invention can be metabolized in vivo. The metabolites of the compounds of formula (I) and formula (II) are also within the scope of the present disclosure. The term "metabolites" refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammalian. Preferably, the term refers to molecules that differ from any molecule that is present in any cell or organism under physiological conditions.
[0184] A treatment defined herein may be applied as the sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Furthermore, the compounds of formula (I) or formula (II) can also be used in combination with existing therapeutic agents for the treatment of conditions associated with mitochondrial dysfunction and cancer, including small molecule therapies or antibody-based therapies.
[0186] The compounds described herein are characterized by a cyanopyrrolidine or cyanopiperidine nucleus.
[0187] The disclosure includes compounds having the formula (I)
[0191] or one of its pharmaceutically acceptable salts, where:
[0192] n is ¹ or ² ;
[0193] when n is ¹ , X is CR ⁴ R ⁵ and when n is ² , X is CR ⁶ R ⁷ CR ⁴ R ⁵ (where CR ⁴ R ⁵ is adjacent to the N atom of the heterocycle);
[0194] R ² represents a hydrogen atom, cyano, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy group, a heteroaryl, heterocyclyl, ⁴ to ¹⁰ membered aryl or optionally substituted ³ to ^{8 membered cycloalkyl ring;}
[0195] R ¹ , R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, cyano, an optionally substituted C1-C3 alkyl or optionally substituted C1-C3 alkoxy group;
[0196] R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, cyano, an optionally substituted C1-C3 alkyl or optionally substituted C1-C3 alkoxy group;
[0197] R ⁹ represents a hydrogen atom, a fluorine atom, cyano, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C3 alkoxy group, a heteroaryl, heterocyclyl, ^4- to ^10- membered ^{aryl, or 3-} to ^8- membered cycloalkyl optionally substituted, or forms an optionally substituted heterocyclic ring with R ¹⁰ wherein the ring optionally comprises one or more additional heteroatoms;
[0198] R ¹⁰ represents a hydrogen atom, C1-C6 alkyl or forms a heterocyclic ring optionally substituted with R ⁹ or R ¹¹ wherein the ring optionally comprises one or more additional heteroatoms;
[0199] Y represents a covalent bond, NR ¹¹ or optionally substituted C1-C3 alkylene;
[0200] R ¹¹ represents a hydrogen atom, an optionally substituted C1-C6 alkyl, a heteroaryl, heterocyclyl, ⁴ to ¹⁰ membered ^{aryl or 3} to ⁸ membered cycloalkyl ring, or forms an optionally substituted heterocyclic ring with R ¹⁰ wherein the ring optionally comprises one or more additional heteroatoms;
[0201] R ¹² represents a heteroaryl ring, heterocyclyl, aryl or ⁴ to ¹⁰ membered cycloalkyl substituted ³ to ⁸ members.
[0202] In a first aspect, the present invention provides a compound having the formula (II)
[0206] a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: m is ⁰ or ¹ ;
[0207] when m is ¹ , Z is -C (R ⁶ ) (R7) -;
[0208] R ² represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
[0209] R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0210] R ¹ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
[0211] R ⁹ represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R ¹⁰ ;
[0212] R ¹⁰ represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R ⁹ , or forms a monocyclic ring with R ¹¹ ;
[0213] Y represents a covalent bond, -C ^{0 -C 3} alkylene -N (R ¹¹ ) -C0-C3 alkylene or C1-C3 alkylene;
[0214] R ¹¹ represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R ¹⁰ ; Y
[0215] wherein R ¹² is defined as in aspects of the invention (i), (ii) and (iii), below.
[0216] According to aspect of the invention (i):
[0217] R ¹² represents a monocyclic, optionally substituted bicyclic, or optionally substituted tricyclic 3- to 14-membered heteroaryl, heterocyclyl or cycloalkyl ring;
[0218] where R ¹² , when substituted, is substituted with one or more of -Q ¹ - (R ¹³ ) p, where:
[0219] p is 0 or 1;
[0220] Q ¹ represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ -, -alkylene (C0-C3) -NR ¹⁴ R ¹⁵ , -alkylene (C0- C3) -CONR ¹⁴ -, -alkylene (C0-C3) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, an oxygen atom, -alkylene (C ⁰ -C ³ ) -CO-, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ , - alkylene (C ⁰ -C ³ ) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO ² R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , - (C ⁰ -C ³ ) alkylene -C (O) R ¹⁴ and (C1-C6) alkylene -NR ¹⁴ SO2R ¹⁵ , NO2, C1-C6 alkylene, -C2-C6 alkenylene, or a -C1-C6 alkyl group optionally replaced;
[0221] q is 0, 1 or 2;
[0222] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group;
[0223] when p is 1, R ¹³ represents a heteroaryl, heterocyclyl, 4 to 10 membered aryl or 3 to 8 membered cycloalkyl ring; wherein R ¹³ may be optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-hydroxyalkyl C6, oxo, cyano, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , - Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ , -Q ² -SO2NR ¹⁷ R ¹⁸ , -Q ² -NR ¹⁷ SO2R ¹⁸ , heterocyclyl, cycloalkyl, heteroaryl, and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH ³ , CONH2, NHC (O) CH ( CH ³ ) ² , and CO ² CH ² CH ³ ;
[0224] Q ² represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; and R ¹⁶ , R ¹⁷ , R ¹⁸ each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl.
[0225] According to aspect of the invention (ii):
[0226] R ¹² represents a 3- to 14-membered monocyclic substituted, optionally substituted bicyclic or optionally substituted tricyclic aryl ring;
[0227] where R ¹² , when substituted, is substituted with one or more of -Q ¹ - (R ¹³ ) p, where:
[0228] p is 0 or 1;
[0229] Q ¹ represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ -, -alkylene (C0-C ³ ) -NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, an oxygen atom, -alkylene (C ⁰ -C ³ ) -CO-, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -C 1 -C6 alkoxy, haloalkoxy C1-C6, C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) - CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) NR ¹⁴ CO2R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -C (O) R ¹⁴ and alkylene ( Ci -C ⁶ ) -NR ¹⁴ SO2R ¹⁵ , NO2, C1-C6 alkylene, -C2-C6 alkenylene, or an optionally substituted -C1-C6 alkyl group;
[0230] q is 0, 1 or 2;
[0231] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group;
[0232] when p is 1, R ¹³ represents a 4 to 10 membered heteroaryl, heterocyclyl or 3 to 8 membered cycloalkyl ring; wherein R ¹³ may be optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-hydroxyalkyl C6, oxo, cyano, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , - Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ , -Q ² -SO2NR ¹⁷ R ¹⁸ , -Q ² -NR ¹⁷ SO2R ¹⁸ , heterocyclyl, cycloalkyl, heteroaryl, and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH ³ ) ² , and CO2CH2CH3;
[0233] Q ² represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; R ¹⁶ , R ¹⁷ , R ¹⁸ each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl; Y
[0234] where the compound does not have the formula:
[0238] According to aspect of the invention (iii):
[0239] R ¹² represents a 3- to 14-membered monocyclic, bicyclic or tricyclic aryl ring;
[0240] where R ¹² is substituted with one or more of -Q ¹ - (R ¹³ ) p, where:
[0241] p is 1;
[0242] Q ¹ represents cyano, oxo, hydroxyl, a covalent bond, -alkylene (C0-C3) -NR ¹⁴ -, -alkylene (C0-C3) -NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, an oxygen atom, -alkylene (C0-C ³ ) -CO-, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , - C1-C6 alkoxy, ^C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -C (C ⁰ -C ³⁾ -SO ² R ^14, -C (C ⁰ -C ³⁾ -NR ¹⁴ COR ^15, -C (C0 -C3) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO2R ¹⁵ , -alkylene (C0-C3) -SO2NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -C ( O) R ¹⁴ and alkylene (CrC6) -NR ¹⁴ SO2R ¹⁵ , NO2, C1-C6 alkylene, -C2-C6 alkenylene, or an optionally substituted -C1-C6 alkyl group;
[0243] q is 0, 1 or 2;
[0244] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group;
[0245] when p is 1, R ¹³ represents a 4 to 10 membered aryl ring; wherein R ¹³ is substituted with one or more substituents selected from C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO ² R ¹⁸ , -Q ² -SO ² R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO ² R ¹⁷ , -Q ² -SO ² NR ¹⁷ R ¹⁸ , -Q ² -NR ¹⁷ SO ² R ¹⁸ , heterocyclyl, cycloalkyl, heteroaryl, and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH ³ ) ² , and CO2CH2CH3;
[0246] Q ² represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; and R ¹⁶ , R ¹⁷ , R ¹⁸ each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl or cycloalkyl.
[0248] For aspects of the invention (i), (ii) and (iii), the optional alkyl substituents of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and Q ¹ , which may be the same or different, are selected from C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano, amino, amido, nitro, and SF5.
[0250] In one embodiment, R ¹ represents a hydrogen atom. In another embodiment, R ¹ represents C1-C3 methyl. In another embodiment, R ¹ represents methyl.
[0252] In one embodiment, R ² represents C1-C3 alkyl, In another embodiment R ² represents C1-C2 (eg, methyl or ethyl). In another embodiment, R ² represents methyl. In another embodiment, R ² represents hydroxyl. In another embodiment, R ² represents C1-C3 alkyl, C1-C2 alkyl (eg, methyl or ethyl), or hydroxyl and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ , R ^9, and R ⁶ and R ⁷ (if present), each independently represent a hydrogen atom In another embodiment R ² represents C1-C3 alkyl or C1-C2 alkyl (eg, methyl or ethyl) and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ and R ⁶ and R ⁷ (if present), each independently represent a hydrogen atom.
[0254] In one embodiment, R ⁵ represents C1-C3 alkyl, In another embodiment R ⁵ represents C1-C2 alkyl (eg, methyl or ethyl). In another embodiment, R ⁵ represents methyl. In another embodiment R ⁵ represents C1-C3 alkyl or C1-C2 alkyl (eg, methyl or ethyl) and R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ and R ⁶ and R ⁷ ( if present) each independently represent a hydrogen atom.
[0256] In one embodiment, R ⁶ and R ⁷ when present represent hydrogen.
[0258] In one embodiment, R ⁸ represents C1-C3 alkyl, In another embodiment R ⁸ represents C1-C2 alkyl (eg, methyl or ethyl). In another embodiment, R ⁸ represents methyl. In another embodiment R ⁸ represents C1-C3 alkyl, C1-C2 alkyl (eg, methyl or ethyl), or a fluorine atom and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ⁶ and R ⁷ (if present) each independently represent a hydrogen atom.
[0260] In one embodiment, R ⁹ represents C1-C3 alkyl, In another embodiment R ⁹ represents C1-C2 alkyl (eg, methyl or ethyl). In another embodiment, R ⁹ represents methyl. In another embodiment, R ⁹ represents C1-C3 alkoxy. In another embodiment, R ⁹ represents C1-C2 alkoxy (eg, methoxy or ethoxy). In another embodiment, R ⁹ represents methoxy. In another embodiment, R ⁹ represents cyclopropyl. In another embodiment, R ⁹ represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C3 alkoxy group or a C3-C4 cycloalkyl, In another embodiment R ⁹ represents C1-C3 alkyl, C1-C2 alkyl (eg, methyl or ethyl), a fluorine or cyclopropyl atom, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^8, and R ⁶ and R ⁷ (if present), each independently represent a hydrogen atom. In one embodiment, R ⁹ is not phenyl, in particular, it is not difluorophenyl.
[0262] Alkyl and alkoxy within the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may be optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.
[0263] In one embodiment, R ⁹ forms a heterocyclic ring optionally substituted with R ¹⁰ wherein the ring optionally comprises one or more additional heteroatoms. In one embodiment, R ⁹ forms a 5-membered heterocyclic ring with R10- In another embodiment, R ⁹ forms a 6-membered heterocyclic ring with R ¹⁰ wherein the ring further comprises an oxygen heteroatom. In another embodiment, R ⁹ forms a heterocyclic ring optionally substituted with R ¹⁰ where the ring optionally comprises one or more additional heteroatoms and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^8, and R ⁶ and R ⁷ ( if present) each independently represent a hydrogen atom. The ring formed by R ⁹ and R ¹⁰ may be optionally substituted with one or more of the substituents defined herein. In one embodiment, optional substituents are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano, amino, amido, nitro, and SF5, wherein the alkyl and alkoxy can be optionally substituted with halogen.
[0265] In one embodiment, R ¹⁰ represents a hydrogen atom, optionally substituted C1-C6 alkyl or forms a heterocyclic ring optionally substituted with R ⁹ or R ¹¹ wherein the ring optionally comprises one or more additional heteroatoms. In one embodiment, R ¹⁰ represents a hydrogen atom. In another embodiment R ¹⁰ represents C1-C3 alkyl. In another embodiment, R ¹⁰ represents methyl. In another embodiment, R ¹⁰ represents ethyl. In another embodiment, the C1-C6 alkyl can be optionally substituted. Optional substituents for alkyl can be selected from C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano, amino, amido, nitro, and SF5, where the alkoxy can be optionally substituted with halogen, particularly fluoro. In particular, C1-C3 may be optionally substituted with C1-C3 alkoxy, eg, methoxy. In one embodiment, R ¹⁰ represents CH2CH2OCH3, In yet another embodiment, R ¹⁰ forms a 5-membered heterocyclic ring with R9 'In another embodiment, R ¹⁰ forms a 6-membered heterocyclic ring with R ⁹ wherein the ring further comprises a heteroatom oxygen.
[0266] In one embodiment, Y is a covalent bond, -NR ¹¹ - or C ¹ -C ³ alkylene, In one embodiment, Y is a covalent bond or C ¹ -C ³ alkylene, In one embodiment, Y is a covalent bond. In another embodiment, Y represents C1-C2 alkylene (eg, methylene or ethylene). In another embodiment, Y is methylene. In another embodiment, Y is -NH-.
[0268] R ¹¹ represents a hydrogen atom, an optionally substituted C1-C6 alkyl, a 4 to 10 membered heteroaryl, heterocyclyl, aryl or 3 to 8 membered cycloalkyl ring or forms a monocyclic or bicyclic heterocyclic ring optionally substituted with R ¹⁰ provided that when the ring is bicyclic it is not substituted with NH2, In one embodiment, R ¹¹ is hydrogen, C1-C6 alkyl or forms a ^5- or ^6- membered monocyclic ring with R ¹⁰
[0269] In one embodiment, R ¹¹ and R ¹⁰ together form a heterocyclyl ring. The ring can be monocyclic or bicyclic. In particular, when R ¹¹ and R ¹⁰ together form a heterocyclyl ring, the ring is a ^5- or ^6- membered monocyclic ring.
[0270] In one embodiment, R ¹¹ and R ¹⁰ together form a ^5- membered heterocyclic ring. In another embodiment, R ¹¹ and R ¹⁰ together form a ^6- membered heterocyclic ring. In one embodiment, when R ¹¹ and R ¹⁰ together form a heterocyclic ring, the ring is not dihydropurine.
[0271] The compounds of formula II may be in the form where m is ⁰ , that is, where the core structure is a cyanopyrrolidine. In such cases, the compounds may have the formula:
[0275] or a pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R8, R9, R10, ^R12 and Y are as defined herein for compounds of formula II.
[0276] Alternatively, the compounds of formula II may be in the form where m is ¹ , that is, the core structure is a cyanopiperidine. In such cases, the compounds may have the formula:
[0280] or one of its pharmaceutically acceptable salts, wherein R1, R2,
[0281] When m is ⁰ , the compounds of formula II can be in the form where R ⁹ and R ¹⁰ together form a ^5- membered heterocyclyl ring that fuses with the cyanopyrrolidine nucleus to create an ^8- membered bicyclic ring. In particular, Y may be a covalent bond and R1, R2, R3, R4, R ⁵ and R ⁸ are each hydrogen. In such cases, the compounds may have the formula:
[0285] or a pharmaceutically acceptable salt thereof, wherein R ¹² is as defined herein for the compounds of formula (II).
[0286] In a further embodiment of the disclosure a compound of formula IID is provided:
[0290] or a pharmaceutically acceptable salt thereof, where R ¹² has been defined above for the compounds of formula (I) or formula (II).
[0291] For compounds of formula (II), R ¹² is a ^3- to ^14- membered ring (eg, ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ^13, or ¹⁴ membered) . When R ¹² is a monocyclic ring, the ring must be substituted. When R ¹² is a bicyclic or tricyclic ring, the ring may be substituted or unsubstituted. In one embodiment, R ¹² is a substituted ring.
[0292] When R ¹² is a heteroaryl or substituted aryl ring, the ring may be monocyclic, bicyclic, or tricyclic and, in the case of a heteroaryl ring, it comprises one or more (eg, ^{1, 2,} or ³ ) selected heteroatoms. between nitrogen, oxygen and sulfur, in particular nitrogen.
[0293] When R ¹² is a heteroaryl or substituted aryl ring, the ring may be monocyclic or bicyclic and, in the case of a heteroaryl ring, comprises one or more (eg, ¹ , ^2, or ³ ) heteroatoms independently selected from among nitrogen, oxygen and sulfur.
[0294] In one embodiment, R ¹² is selected from phenyl, pyrrolidinyl, thiazolyl, pyridinyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, indolyl, benzimidazolyl, quinolinyl, azetidinyl, indazolyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridyl, piperazolopyridinyl, imidazopyridinyl, imidazopyridinyl, , tetrahydropyridoindolyl, benzomorpholinyl and pyrrolopyridinyl. In one embodiment, R ¹² is selected from phenyl, pyrrolidinyl, thiazolyl, pyridinyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, indolyl, benzimidazolyl, and quinolinyl.
[0295] Typical examples of R ¹² include Fen ³ -yl, Fen ⁴ -yl, pyrrolidin- ¹ -yl, thiazol - ² -yl, thiazol - ⁵ -yl, pyridin - ² -yl, pyridin - ³ -yl, pyridin - ⁴ -yl, isoxazol- ⁵ -yl, oxazol- ² -yl, pyrazol- ⁴ -yl, pyrazol- ⁵ -yl, pyrimidin- ² -yl, pyradazin- ³ -yl, imidazol- ⁴ -yl, indole- ² -yl, benzimidazol- ² -yl, quinolin- ⁴ -yl and quinolin- ⁶ -yl.
[0296] In particular, R ¹² can be selected from azetidinyl and pyrrolidinyl. In one embodiment, R ¹² is azetidinyl. In another embodiment, R ¹² is pyrrolidinyl. When R ¹² is azetidinyl or pyrrolidinyl, preferably Y is a covalent bond that is attached to the nitrogen atom of the azetidinyl or pyrrolidinyl ring.
[0297] In one embodiment, when R ¹² is pyridinyl, the pyridinyl is pyridin- ^{2 -yl.}
[0298] Examples of R ¹² include those shown below:
[0299]
[0300]
[0303] Where * denotes the direct anchor point to the nucleus of cyanopyrrolidine or cyanopiperidine through -YC (O) N (R ¹⁰ ) -. Monocyclic rings are substituted with at least one -Q ¹ - (R ¹³ ) p and bicyclic and tricyclic rings can be unsubstituted or substituted with one or more -Q ¹ - (R ¹³ ) p substituents as described herein. . Hydrogen atoms attached to ring nitrogen atoms have not been shown. One of skill in the art will understand which ring nitrogen atoms are suitable for substitution and, when unsubstituted, nitrogen can be attached to a hydrogen atom to complete its valence, where appropriate.
[0305] Additional examples of R ¹² include those shown below:
[0307]
[0308]
[0310] When substituted, R ¹² may be substituted with one or more -Q ¹ - (R ¹³ ) p, where -Q ¹ - (R ¹³ ) p in each case may be the same or different.
[0311] p is 0 or 1 (when p is 1, Q ¹ is a covalent or connecting bond and R ¹³ is present, when p is 0, Q ¹ is present and R ¹³ is absent).
[0312] Preferably p is 1.
[0313] Q ¹ represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ -, -alkylene (C0-C3) -NR ¹⁴ R ¹⁵ , -alkylene (C0- C3) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, -alkylene (C ⁰ -C ³ ) -O- C0-C3 alkylene, -alkylene (C ⁰ -C ³ ) -CO-, -alkylene (C ⁰ -C ³ ) -S (O) q-, -alkylene (C0-C3) -SO2NR ¹⁴ , -alkoxy C1- C6, C1-C ⁶ haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ , -alkylene (C0-C3) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C0-C3) -NR ¹⁴ SO2NR ¹⁵ R ¹⁶ , -alkylene (C0-C3) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO2R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ , -alkylene (C ⁰ -C ³ ) -C (O) R ¹⁴ and (C1-C6) alkylene -NR ¹⁴ SO2R ¹⁵ , NO2, or an optionally substituted C1-C6 alkylene, -C2-C6 alkenylene or -C1-C6 alkyl group; where q is 0, 1, or 2.
[0314] Q ¹ can represent a halogen atom, cyano, oxo, a covalent bond, -NR ¹⁴ -, -NR ¹⁴ R ¹⁵ , -CONR ¹⁴ -, -NR ¹⁴ CO-, an oxygen atom, -CO-, -S (O) q-, -SO2NR14, -C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -SO2R14, -NR ¹⁴ COR ¹⁵ , -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -NR ¹⁴ SO2NR ¹⁵ R ¹⁶ - CONR ¹⁴ R ¹⁵ , -CO2R14, -NR ¹⁴ CO2R ¹⁵ , -SO2NR ¹⁴ R ¹⁵ , -CONR ¹⁴ , -C (O) R ¹⁴ and -NR ¹⁴ SO2R ¹⁵ , NO2, or a C1-C6 alkylene, -alkenylene group C2-C6 or -C1-C6 alkyl optionally substituted; where
[0315] q is 0, 1, or 2.
[0316] In one embodiment, Q ¹ represents a halogen atom, cyano, oxo, a covalent bond, an oxygen atom, a -alkylene (C ⁰ -C ³ ) -O-C0-C3 alkylene, C1-C6 alkoxy, alkoxy group C1-C4, C1-C2 alkoxy, C1-C6 haloalkoxy, C1-C4 haloalkoxy, C1-C2 haloalkoxy, -C1-C6 hydroxyalkyl, C1-C4 hydroxyalkyl, C1-C2 hydroxyalkyl, C1-C6 alkylene, C1-C4 alkylene, C1-C2 alkylene, C2-C6 alkenylene or C2-C4 alkenylene which may be optionally substituted with hydroxy, a halogen atom (e.g. fluorine, chlorine or bromine), C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, C1-C6 haloalkyl, C1-C4 haloalkyl, C1-C2 haloalkyl, NR ¹⁴ -, -NR ¹⁴ R ¹⁵ -, -CONR ¹⁴ -, -NR ¹⁴ CO-, CO-, -S (O) q-, -SO2NR14,
[0318] -NR ¹⁴ SO2-, -SO2R14, -NR ¹⁴ COR ¹⁵ , -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -NR ¹⁴ SO2NR ¹⁵ R ¹⁶ -CONR ¹⁴ R ¹⁵ , -CO2R14, -NR ¹⁴ CO2R ¹⁵ ,
[0319] -SO2NR ¹⁴ R ¹⁵ , -CONR ¹⁴ , -C (O) R ¹⁴ , -NR ¹⁴ SO2R ¹⁵ , or NO2.
[0321] In one embodiment, Q ¹ represents a halogen atom, cyano, oxo, a covalent bond, an oxygen atom, a group -O-methylene, -O-ethylene, C1-C6 alkoxy, C1-C4 alkoxy, C1-alkoxy. C2, C1-C6 haloalkoxy, C1-C4 haloalkoxy, C1-C2 haloalkoxy, C1-C6 -hydroxyalkyl, C1-C4 hydroxyalkyl, C1-C2 hydroxyalkyl, C1-C6 alkylene, C1-C4 alkylene, C1-C2 alkylene, C2 alkenylene -C6 or C2-C4 alkenylene which may be optionally substituted with hydroxy, a halogen atom (eg, fluorine, chlorine or bromine), C1-C6 alkyl, C1-C4 alkyl, C1-C2 alkyl, C1-haloalkyl C6, C1-C4 haloalkyl, C1-C2 haloalkyl, NR ¹⁴ -, -NR ¹⁴ R ¹⁵ -, -CONR ¹⁴ -, -NR ¹⁴ CO-, CO-, -S (O) q-, -SO2NR14, -SO2R14 ,
[0323] -NR ¹⁴ COR ¹⁵ , -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -NR ¹⁴ SO2NR ¹⁵ R ¹⁶ -CONR ¹⁴ R ¹⁵ , -CO2R14, -NR ¹⁴ CO2R ¹⁵ , -SO2NR ¹⁴ R ¹⁵ , -CONR ¹⁴ ,
[0324] -C (O) R ¹⁴ , -NR ¹⁴ SO2R ¹⁵ , or NO2.
[0326] In another embodiment, Q ¹ is selected from halogen, cyano, oxo, C1-C6 alkyl optionally substituted with fluorine, C1-C6 alkoxy optionally substituted with fluorine, -NR ¹⁴ COR ¹⁵ , a covalent bond, an oxygen atom, -alkylene (C0-C ³ ) -O-C0-C3 alkylene, -NR ¹⁴ -, C1-C6 alkylene, -NR ¹⁴ SO2- and -NR ¹⁴ R ¹⁵ -.
[0328] In another embodiment, Q ¹ is selected from halogen, oxo, a covalent bond, -NR ¹⁴ R ¹⁵ -, an oxygen atom, C1-C6 alkoxy, C1-C4 alkoxy, C1-C2 alkoxy, -NR ¹⁴ COR ¹⁵ or C1-C6 alkyl, C1-C4 alkyl or C1-C2 alkyl.
[0330] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or an optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkylene group. The alkyl or alkenylene group can be optionally substituted with halogen, hydroxyl, thiol, cyano, amino, amido, nitro, and SF5.
[0332] In another embodiment, Q ¹ can be selected from a fluorine atom, a chlorine atom, a bromine atom, cyano, oxo, methyl, butyl, CF3, methoxy, OCF3, NMeC (O) CH (CH ³ ) ² , -NHCOCH (CH ³ ) ² , a covalent bond, an oxygen atom, -O-methylene, -NH-, C1-C2 alkylene, -NMeS (O) 2-, -OCH2- and -N ( ^c H3) ^c H2-.
[0334] In another embodiment, Q ¹ can be selected from a fluorine atom, a chlorine atom, oxo, a covalent bond, an oxygen atom, methoxy, -NHCOCH (CH ³ ) ² and -N (CH ³ ) CH ² - .
[0336] When R ¹² is phenyl or pyridinyl, the phenyl or pyridinyl ring is preferably substituted with fluoro at one of the ortho positions of the ring. The phenyl or pyridinyl ring may be further substituted with -Q ¹ - (R ¹³ ) p as described above.
[0338] R ¹³ represents a 4- to 10-membered heteroaryl ring (eg, 4, 5, 6, 7, 8, 9, or 10 membered), heterocyclyl, aryl, or 3- to 8-membered cycloalkyl (eg, 3, 4, 5, 6, 7 or 8 members) optionally substituted.
[0340] In one embodiment, R ¹³ represents a 4- to 10-membered heteroaryl, heterocyclyl, aryl, or 3- to 8-membered cycloalkyl ring substituted with one or more substituents selected from halogen, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy , C1-C6 haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally aryl substituted, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ , -Q ² -SO2NR ¹⁷ R ¹⁸ and -Q2-NR ¹⁷ SO2R ¹⁸
[0342] Q ² represents a covalent bond, an oxygen atom, carbonyl, or a C1-C6 alkylene or C2-C6 alkenylene group.
[0343] In one embodiment, Q ² can be selected from a covalent bond, an oxygen atom, carbonyl, or an optionally substituted C1-C6 alkylene (eg, C1-C3 alkylene, C1-C4 alkylene, C1-C2 alkylene), C2-C6 alkenylene or C2-C4 alkenylene, Alkylene and alkenylene can be optionally substituted with halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5.
[0345] In another embodiment Q ² is selected from a covalent bond, an oxygen atom, or a carbonyl. In particular, Q ² is a covalent bond.
[0347] R ¹⁷ , R ¹⁸ and R ¹⁹ each independently represent hydrogen, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted cycloalkyl.
[0349] R ¹⁷ , R ¹⁸ and R ¹⁹ may each independently represent hydrogen, C1-C6 alkyl or a 3- to 10-membered, particularly 3- to 6-membered heterocyclyl, heteroaryl, aryl or cycloalkyl ring, wherein the ring is optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, thiol, cyano, amino, amido, nitro, and SF5, wherein the alkyl or alkoxy is optionally substituted with fluorine.
[0350] R ¹³ may be substituted with halogen, cyano, C1-C3 alkyl optionally substituted with fluorine, C1-C3 alkoxy optionally substituted with fluorine, or -Q ² -R ¹⁷ , where Q ² represents a covalent bond, an oxygen atom, carbonyl or a C1-C6 alkylene or C2-C6 alkenylene group and R ¹⁷ represents an optionally substituted 3- to 10-membered heterocyclyl, heteroaryl, aryl or cycloalkyl ring, wherein the optional substituents are selected from C1-C6 alkyl, C1 alkoxy -C6, halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5, where the alkyl or alkoxy are optionally substituted with fluorine.
[0352] In particular, R ¹³ can be substituted with fluorine, chlorine, cyano, methyl, CF3, ethyl, methoxy or -Q ² -R ¹⁷ , where Q ² is a covalent bond, oxygen atom or carbonyl and R ¹⁷ is selected from optionally substituted morpholinyl, cyclopropyl, phenyl or pyridinyl and the optional substituents are one or more fluorine atoms.
[0354] In one embodiment, R ¹³ is unsubstituted.
[0356] In one embodiment, R ¹³ is substituted with other optionally substituted 3- to 8-membered heteroaryl, heterocyclyl, aryl, or cycloalkyl rings, either directly attached or through a connecting group. The connecting group can be an oxygen atom or a carbonyl. The linking group can be an oxygen atom or -CO-.
[0358] In one embodiment, R ¹³ is selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, morpholinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl, benzopyrazolyl, isoindolinyl, tetrahydroquinolinyl, homopiperazinyl, pyrimidinyl, imidazopyridazoidinyl, pyrimidinyl, imidazopyridazolidinyl, imidazopyridazolidinyl, imidazopyridazolidinyl, , pyrazolopyrimidinyl, pyrrolopyrimidinyl, imidazopyrazinyl, and dihydroisoquinolinyl.
[0360] In one embodiment, R ¹³ is selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, morpholinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl, benzopyrazolyl, isoindolinyl, tetrahydroquinolinyl, and homopiperazinyl.
[0362] In the present invention, the compounds of the formulas described herein do not include compounds of the following structures:
[0364]
[0367] The compounds of the formulas described herein do not include the following compounds:
[0369] N - [(3R) -1-cyano-3-pyrrolidinyl] -4-fluoro-benzamide;
[0371] N- (1-cyano-3-pyrrolidinyl) - [1,1'-biphenyl] -4-carboxamide;
[0373] N- (1-cyano-3-piperidinyl) - [1,1'-biphenyl] -4-carboxamide;
[0375] N - [(3R) -1-cyano-3-pyrrolidinyl] -3 - ({[(3R) -1-cyano-3-pyrrolidinyl] amino} sulfonyl) benzamide;
[0376] N - [(3R) -1-cyano-3-pyrrolidinyl] -3 - ([(3R) -3-pyrrolidinylamino] sulfonyl) -benzamide; or
[0377] 1 - ((3S, 4R) -1 -cyano-4- (3,4-difluorophenyl) pyrrolidin-3-yl) -3- (1 ', 4-dimethyl-1-phenyl-1 H, 1'H- [3,4'-bipyrazol] -5-yl) ureayl) urea. that is, composed of the following structures:
[0379]
[0381] In the present disclosure, the compounds of formulas (I), (IB) and (IID), including their subgeneric embodiments, do not include compounds of the following structures:
[0385] Mentioned embodiments of the disclosure include compounds of formulas (I), (IB) and (IID) wherein:
[0386] n, X, R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ and Y are defined above for the compounds of formula (I);
[0387] R ¹² represents:
[0388] i) a heteroaryl, 4 to 10 membered heterocyclyl or 3 to 8 membered cycloalkyl ring substituted with one or more of Q ¹ - (R ¹³ ) p;
[0389] ii) a 4 to 10 membered aryl ring substituted with two or more Q ¹ - (R ¹³ ) p;
[0390] iii) a 5, 7, 8, 9 or 10 membered aryl ring individually substituted with Q ¹ - (R ¹³ ) p; or
[0391] iv) a 6-membered aryl ring substituted individually with Q ¹ - (R13 ') p;
[0392] where p is 0 or 1;
[0393] Q ¹ represents a halogen atom, cyano, oxo, a covalent bond, -NR ¹⁴ -, -NR ¹⁴ R ¹⁵ , -CONR ¹⁴ -, -NR ¹⁴ CO-, an oxygen atom, -CO-, -S ( O) q-, -SO2NR14-, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -SO2R14, -NR ¹⁴ COR ¹⁵ , -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -NR ¹⁴ SO2NR ¹⁵ R ¹⁶ -, -CONR ¹⁴ R ¹⁵ , -CO2R14, -NR ¹⁴ CO2R ¹⁵ , -SO2NR ¹⁴ R ¹⁵ , -CONR ¹⁴ , -C (O) R ¹⁴ and -NR ¹⁴ SO2R ¹⁵ , NO2 or an optionally substituted C1-C6 alkylene group, -C2-C6 alkenylene or -C1-C6 alkyl; Q1 'represents a chlorine or bromine atom, cyano, oxo, a covalent bond, -NR ¹⁴ -, -NR ¹⁴ R ¹⁵ , -CONR ¹⁴ -, -NR ¹⁴ CO-, an oxygen atom, -CO-, -S (O) q-, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -SO2R14, -NR ¹⁴ R ¹⁵ , -NR ¹⁴ COR ¹⁵ , -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -CONR ¹⁴ R ¹⁵ , -CO2R145, -NR ¹⁴ CO2R ¹⁵ , -SO2NR ¹⁴ R ¹⁵ , -CONR ¹⁴ , -C (O) R ¹⁴ and -NR ¹⁴ SO2R ¹⁵ or a C1-C6 alkylene group , -C2-C6 alkenylene or -C1-C6alkyl optionally substituted;
[0394] q is 0, 1 or 2;
[0395] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or an optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkylene group; Y
[0396] when p is 1:
[0397] R ¹³ represents a 4 to 10 membered heteroaryl, heterocyclyl, aryl or 3 to 8 membered cycloalkyl ring (when p is 0, Q ¹ is present and R ¹³ is absent), which is optionally substituted with one or more selected substituents among halogen, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO ² R ¹⁸ , -Q ² -SO ² R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R17, -Q ² -SO2NR ¹⁷ R ¹⁸ and -Q ² -NR ¹⁷ SO2R ¹⁸ ;
[0398] R13 'represents an optionally substituted 3- to 8-membered heteroaryl, 4- to 10-membered heterocyclyl or cycloalkyl ring, an optionally substituted 5, 7, 8, 9, or 10-membered aryl ring, or a substituted 6-membered ring ( when p is 0, Q1 'is present and R13' is absent) substituted with one or more substituents selected from halogen, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkoxy, optionally substituted C1-C6 alkyl , optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO ² R ¹⁸ , -Q ² -SO ² R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R17, -Q ² -SO2NR ¹⁷ R ¹⁸ and -Q ² -NR ¹⁷ SO2R ¹⁸ ;
[0399] Q ² represents a covalent bond, an oxygen atom, carbonyl or a C1-C6 alkylene or C2-C6 alkenylene group; and R ¹⁷ , R ¹⁸ , R ¹⁹ each independently represent hydrogen, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted cycloalkyl.
[0400] In a particular embodiment of the disclosure, a compound of formula (IID) is provided wherein:
[0401] R ¹² is selected from phenyl or pyridinyl and is substituted with one or two Q ¹ (R ¹³ ) p, where p is 1;
[0402] each Q ¹ is independently selected from a covalent bond, a fluorine atom, C1-C3 alkoxy or C1-C2 alkoxy (eg, methoxy or ethoxy); Y
[0403] R ¹³ is selected from a 5- or 6-membered heteroaryl or heterocyclyl which is optionally substituted with C ¹ -C ³ alkyl.
[0404] Mentioned embodiments of the invention include compounds of formulas (II) or (III) wherein: m, Z, R1, R2, R3, R4, R5, R8, R9, R10 and Y are defined above for compounds of formula (II);
[0405] R12 represents:
[0406] i) a 3- to 10-membered monocyclic heterocyclyl or cycloalkyl ring substituted with one or more of Q1- (R13) p, or bicyclic heterocyclic or cycloalkyl ring optionally substituted with one or more of Q1- (R13) p;
[0407] ii) a 5- to 14-membered monocyclic aryl ring substituted with two or more Q1- (R13) p, or bicyclic or tricyclic aryl ring optionally substituted with two or more Q1- (R13) p;
[0408] iii) a 5 or 7 to 14 membered monocyclic aryl ring substituted with one or more Q1- (R13) p, or bicyclic or tricyclic aryl ring optionally substituted with one or more Q1- (R13) p;
[0409] iv) a 6-membered aryl ring monosubstituted with Q1 '- (R13') p;
[0410] v) a 5- to 14-membered heteroaryl ring substituted with one or two Q1- (R13) p;
[0411] vi) a 6 to 14 membered heteroaryl ring substituted with one or more Q1- (R13) p; or
[0412] vii) a 5-membered heteroaryl ring substituted with one or more Q1M- (R13 ") p.
[0413] where p is 0 or 1;
[0414] Q ¹ represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C0-C3) -NR ¹⁴ -, -alkylene (Cü-C ³ ) -NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ - C ³ ) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, -alkylene (C ⁰ -C ³ ) -O -C0-C3 alkylene, -alkylene (C ⁰ -C ³ ) -CO-, -alkylene (C1-C6) -S (O) q-, -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ , - C1-C6 alkoxy, ^C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -C (C ⁰ -C ³⁾ -SO ² R ^14, -C (C ⁰ -C ³⁾ -NR ¹⁴ COR ^15, -C (C ⁰ -C ³ ) -NR ¹⁴ CONR ¹⁵ R ¹⁶ ,
[0415] -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , - alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO2R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ , -alkylene (C ⁰ - C ³ ) -C (O) R ¹⁴ and (C1-C6) alkylene -NR ¹⁴ SO2R ¹⁵ , NO2, or an optionally substituted C1-C6 alkylene, -C2-C6 alkenylene or -C1-C6 alkyl group;
[0417] Q1 'represents a chlorine or bromine atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C0-C3) -NR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ R ¹⁵ , -alkylene ( C ⁰ -C ³ ) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, -alkylene (C0-C3) - O-C0-C3 alkylene, -alkylene (C0-C3) -CO-, -alkylene (C1-C6) -S (O) q-, -alkylene (C1-C6) -SO2NR ¹⁴ , -alkoxy C1-C6, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C ⁰ -C ³ ) -SO ² R ¹⁴ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ COR ¹⁵ ,
[0418] -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CONR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO2R14, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO ² R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene ( C ⁰ -C ³ ) -CONR ¹⁴ , -alkylene (C ⁰ -C ³ ) -C (O) R ¹⁴ and alkylene (C1-C6) -NR ¹⁴ SO2R ¹⁵ , NO2, or a C1-C6 alkylene group, - C2-C6 alkenylene or -C1-C6 alkyl optionally substituted;
[0420] Q1 "represents a halogen, cyano, oxo, hydroxyl atom, a covalent bond, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ -, -alkylene (C0-C ³ ) -NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ -, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO-, -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² -, -alkylene (C ⁰ -C ³ ) -O-C0-C3 alkylene, -alkylene (C0-C3) -CO-, -alkylene (C1-C6) -S (O) q-, -alkylene (C0-C3) -SO2NR ¹⁴ , -alkoxy C1-C6 , ^C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -C (C ⁰ -C ³⁾ -SO ² R ^14, -C (C0-C3) -NR ¹⁴ COR ^15, -C (C0-C3) -NR ¹⁴ CONR ¹⁵ R ¹⁶ ,
[0421] -alkylene (C ⁰ -C ³ ) -NR ¹⁴ SO ² NR ¹⁵ R ¹⁶ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CO ² R ¹⁴ , - alkylene (C ⁰ -C ³ ) -NR ¹⁴ CO2R ¹⁵ , -alkylene (C ⁰ -C ³ ) -SO ² NR ¹⁴ R ¹⁵ , -alkylene (C ⁰ -C ³ ) -CONR ¹⁴ , -alkylene (C ⁰ - C ³ ) -C (O) R ¹⁴ and (C1-C6) alkylene -NR ¹⁴ SO2R ¹⁵ , NO2, or an optionally substituted C1-C6 alkylene, -C2-C6 alkenylene or -C2-C6 alkyl group;
[0423] q is 0, 1 or 2;
[0425] R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or an optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkylene group; Y
[0427] when p is 1:
[0429] R ¹³ represents a heteroaryl, heterocyclyl, 4 to 10 membered aryl or 3 to 8 membered cycloalkyl ring, which is optionally substituted with one or more substituents selected from halogen, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy , C1-C6 haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally aryl substituted, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ ,
[0430] -Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ , -Q ² -SO2NR ¹⁷ R ¹⁸ and -Q ² -NR ¹⁷ SO2R ¹⁸ ;
[0432] R13 'represents an optionally substituted 3- to 8-membered heteroaryl, 4- to 10-membered heterocyclyl or cycloalkyl ring, an optionally substituted 5, 7, 8, 9, or 10-membered aryl ring, or a substituted 6-membered ring ( when p is 0, Q1 'is present and R13' is absent) substituted with one or more substituents selected from halogen, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkoxy, optionally substituted C1-C6 alkyl , optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO ² R ¹⁸ , -Q ² -SO ² R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO ² R ¹⁷ and -Q ² -NR ¹⁷ SO ² R ¹⁸ ;
[0434] R13 "represents an optionally substituted heteroaryl, 4- to 10-membered aryl or 3- to 8-membered cycloalkyl ring, an optionally substituted 6 to 10-membered heteroaryl ring, or a substituted 5-membered heterocyclyl ring wherein the substituents are selected among halogen, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkoxy, optionally substituted C2-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, -Q ² -R ¹⁷ , -Q ² -NR ¹⁷ CONR ¹⁸ R ¹⁹ , -Q ² -NR ¹⁷ R ¹⁸ , -Q ² -COR ¹⁷ , -Q ² -NR ¹⁷ COR ¹⁸ , -Q ² -NR ¹⁷ CO2R ¹⁸ , -Q ² -SO2R ¹⁷ , Q ² -CONR ¹⁷ R ¹⁸ , -Q ² -CO2R ¹⁷ and -Q ² -NR ¹⁷ SO2R ¹⁸
[0436] Q ² represents a covalent bond, an oxygen atom, carbonyl or a C1-C6 alkylene or C2-C6 alkenylene group; Y
[0437] R ¹⁷ , R ¹⁸ , R ¹⁹ each independently represent hydrogen, optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted cycloalkyl.
[0438] Examples of new compounds of formula (I) and / or formula (II) include: (R) -N- (1-cyanopyrrolidin-3-yl) -5-phenMpicolinamide
[0439] (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamide 2'-chloro-N- (1-cyanopyrrolidin-3 -yl) - [1,1'-biphenyl] -4-carboxamide
[0440] 6- (benzyl (methyl) amino) -N- (1-cyanopyrrolidin-3-yl) nicotinamide
[0441] (R) -N- (1-cyanopyrrolidin-3-yl) -3-phenylazetidine-1-carboxamide
[0442] N - ((R) -1-cyanopyrrolidin-3-yl) -4 - ((2S, 6R) -2,6-dimethylmorpholino) -3-fluorobenzamide N- (1-cyanopyrrolidin-3-yl) -4-phenylthiazole -2-carboxamide
[0443] 3- (3-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) isoxazole-5-carboxamide
[0444] N- (1-cyanopyrrolidin-3-yl) -1-phenyl-1 H-imidazole-4-carboxamide
[0445] N- (1-cyanopyrrolidin-3-yl) -1- (2,4-difluorobenzyl) -5-oxopyrrolidine-3-carboxamide N- (1-cyanopyrrolidin-3-yl) -5-oxo-1-phenylpyrrolidin-3 -carboxamide
[0446] N- (1-cyanopyrrolidin-3-yl) -4- (3,5-dimethylisoxazol-4-yl) benzamide
[0447] 3'-chloro-N- (1-cyanopyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide
[0448] N- (1-cyanopyrrolidin-3-yl) -2'-methoxy- [1,1'-biphenyl] -4-carboxamide
[0449] N- (1-cyanopyrrolidin-3-yl) -4-phenoxybenzamide
[0450] 2 - ([1,1'-biphenyl] -4-yl) -N- (1-cyanopyrrolidin-3-yl) acetamide
[0451] N- (1-cyanopyrrolidin-3-yl) -2-phenylquinoline-4-carboxamide
[0452] 6- (4-carbamoylpiperidin-1-yl) -N- (1-cyanopyrrolidin-3-yl) nicotinamide
[0453] N- (1-cyanopyrrolidin-3-yl) -6- (4- (2,4-difluorophenyl) piperazin-1-yl) nicotinamide 4- (5 - ((1-cyanopyrrolidin-3-yl) carbamoyl) pyridin- Ethyl 2-yl) piperazin-1-carboxylate N- (1-cyanopyrrolidin-3-yl) -6- (2- (pyridin-3-yl) pyrrolidin-1-yl) nicotinam ida
[0454] N- (1-cyanopyrrolidin-3-yl) -6- (4-phenoxypiperidin-1-yl) nicotinamide
[0455] N- (1-cyanopyrrolidin-3-yl) -6- (4- (pyridin-4-yl) piperidin-1 -yl) nicotinam ida
[0456] 6- (benzyl (methyl) amino) -N- (1-cyanopyrrolidin-3-yl) picolinamide
[0457] N- (1-cyanopyrrolidin-3-yl) -6- (3,4-dihydroisoquinolin-2 (1 H) -yl) picolinamide
[0458] N- (1-cyanopyrrolidin-3-yl) -6- (4-phenoxypiperidin-1-yl) picolinamide
[0459] N- (1-cyanopyrrolidin-3-yl) -2- (3,4-dihydroisoquinolin-2 (1 H) -yl) isonicotinamide 2- (4-acetyl-1,4-diazepan-1 -yl) -N- (- (1-cyanopyrrolidin-3-yl) isonicotinamide
[0460] (R) -N- (1-cyanopyrrolidin-3-yl) -6-phenylpicolinamide
[0461] (R) -N- (1-cyanopyrrolidin-3-yl) -4-phenylpicolinamide
[0462] (R) -N- (1-cyanopyrrolidin-3-yl) -4-morpholinobenzamide
[0463] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4-morpholinobenzamide
[0464] (R) -N- (1-cyanopyrrolidin-3-yl) -3-phenylisoxazole-5-carboxamide
[0465] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (pyridin-4-yl) isoxazole-3-carboxamide
[0466] (R) -N- (1-cyanopyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide
[0467] (R) -6- (4-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) nicotinamide (R) -2- (2-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) thiazole-5-carboxamide
[0468] (R) -4- (3-chloropyridin-4-yl) -N- (1-cyanopyrrolidin-3-yl) benzamide
[0469] (R) -4- (3-chloropyridin-4-yl) -N- (1-cyanopyrrolidin-3-yl) -3-methoxybenzamide
[0470] (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (2-methylpyridin-4-yl) benzamide
[0471] (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (2-morpholinopyridin-4-yl) benzamide
[0472] (R) -N- (1-cyanopyrrolidin-3-yl) -4-fluoro-3- (pyridin-4-yl) benzamide
[0473] (R) -N- (1-cyanopyrrolidin-3-yl) -4-fluoro-3- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0474] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0475] (R) -N- (1 -cyanopyrrolidin-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2-carboxamide
[0476] N - ((R) -1-cyanopyrrolidin-3-yl) -3-phenylpyrrolidin-1-carboxamide
[0477] (S) -N- (1-cyanopyrrolidin-3-yl) -4- (pyridin-4-yl) benzamide
[0478] (S) -N- (1-cyanopyrrolidin-3-yl) -6-phenylpicolinamide
[0479] (R) -4- (3-chloropyridin-4-yl) -N- (1-cyanopyrrolidin-3-yl) -N-methylbenzamide
[0480] (R) -1 - (1 -cyanopyrrolidin-3-yl) -3- (imidazo [1,2-a] pyridin-2-yl) -1-methylurea
[0481] (3aR, 6aR) -1 - ([1,1'-biphenyl] -3-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile
[0482] (3aR, 6aR) -1- (3-phenyl-1H-pyrazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1H) -carbonitrile (3aR, 6aR) -1- (3- phenylisoxazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1H) -carbonitrile (3aR, 6aR) -1 - (1-phenyl-1H-imidazole-4-carbonyl) hexahydropyrrolo [3,4 -b] pyrrolo-5 (1 H) -carbonitrile (3aR, 6aR) -1- (3- (4-methoxyphenyl) -1 H-pyrazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 ( 1 H) -carbonitrile (3aR, 6aR) -1- (3- (4-methoxyphenyl) isoxazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile (3aR, 6aR) - 1- (4-fluoro-3- (pyridin-4-yl) benzoyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile (3aR, 6aR) -1 - (4-fluoro-3- (1-methyl-1 H-pyrazol-4-yl) benzoyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (11 H) -carbonitrile (3aR, 6aR) -1- (4- (3-chloropyridin-4 -yl) -3-methoxybenzoyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1H) -carbonitrile (3aR, 6aR) -1 - (3-methoxy-4- (1-methyl-1H-pyrazole- 4-yl) benzoyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1H) -carbonitrile (3aR, 6aR) -1- (2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonyl) hexahydropyrrolo [3,4-b] pyrrole o-5 (1 H) -carbonitrile (R) -N- (1-cyanopyrrolidin-3-yl) -3- (N-methylisobutyramido) benzamide
[0483] (R) -N- (1-cyanopyrrolidin-3-yl) -5-phenylpyrimidine-2-carboxamide
[0484] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (pyridin-4-yl) isoxazole-5-carboxamide
[0485] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (pyridin-3-yl) isoxazole-5-carboxamide
[0486] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (pyridin-2-yl) isoxazole-5-carboxamide
[0487] N- (1-cyanopyrrolidin-3-yl) -5-phenylpyridazine-3-carboxamide
[0488] N- (1-cyanopyrrolidin-3-yl) -N-methyl- [1,1'-biphenyl] -4-carboxamide
[0489] N - ((3S, 4R) -1-cyano-4-methylpyrrolidin-3-yl) -2-phenylthiazole-5-carboxamide
[0490] N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -2-phenylthiazole-5-carboxamide
[0491] N - ((3S, 4R) -1-cyano-4-methylpyrrolidin-3-yl) -5-phenylthiazole-2-carboxamide
[0492] N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -5-phenylthiazole-2-carboxamide
[0493] (R) -N- (1-cyanopyrrolidin-3-yl) -2- (isoindolin-2-yl) isonicotinamide
[0494] (R) -N- (1-cyanopyrrolidin-3-yl) -2- (3,4-dihydroisoquinolin-2 (1 H) -yl) isonicotinamide
[0495] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (4-methyl-1 H-imidazol-1-yl) benzamide
[0496] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0497] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0498] (R) -N- (1-cyanopyrrolidin-3-yl) -2,5-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0499] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (1,3-dimethyl-1H-pyrazol-4-yl) -3-fluorobenzamide
[0500] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (1,3-dimethyl-1H-pyrazol-4-yl) -2-fluorobenzamide
[0501] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (1-ethyl-1 H-pyrazol-4-yl) -2-fluorobenzamide
[0502] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (1 - (2-methoxyethyl) -1 H-pyrazol-4-yl) benzamide
[0503] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1 H-pyrazol-4-yl) -1 H-benzo [d] imidazole-2-carboxamide (R) -N - (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide
[0504] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (5- (trifluoromethyl) -1 H-pyrazol-4-yl) benzamide
[0505] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (1-methyl-1 H-indazol-5-yl) benzamide
[0506] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-N-methyl-4- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0507] (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-6- (1-methyl-1 H-pyrazol-4-yl) -1 H-benzo [d] imidazole-2-carboxamide ( R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-3-phenoxyazetidine-1-carboxamide
[0508] (3aR, 6aR) -5-cyano-N- (2-fluoro-4- (trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (R) -N- (1-cyanopyrrolidine -3-yl) -2-fluoro-4- (pyrimidin-2-ylamino) benzamide
[0509] N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -2-fluoro-4 - ((R) -3-methoxypyrrolidin-1-yl) benzamide
[0510] 2- (2-chlorophenyl) -N - ((3R, 4R) -1-cyano-4-hydroxypyrrolidin-3-yl) thiazole-5-carboxamide
[0511] N- (1-cyano-3-methylpyrrolidin-3-yl) -2-fluoro-4- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0512] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (4-methoxyphenyl) -1 H-pyrazole-3-carboxamide
[0513] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (pyridin-2-yl) -1 H-pyrazole-3-carboxamide
[0514] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (2-methoxyphenyl) -1 H-pyrazole-3-carboxamide
[0515] (R) -N- (1cyanopyrrolidin-3-yl) -5- (2-fluorophenyl) -1 H-pyrazole-3-carboxamide
[0516] (R) -N- (1-cyanopyrrolidin-3-yl) -6-morpholinonicotinamide
[0517] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (4-methoxyphenyl) isoxazole-5-carboxamide
[0518] (R) -N- (1-cyanopyrrolidin-3-yl) -1 H-indazole-3-carboxamide
[0519] (R) -N- (1-cyanopyrrolidin-3-yl) -5-phenyl-1H-pyrazole-3-carboxamide
[0520] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (pyridin-3-yl) -1 H-pyrazole-3-carboxamide
[0521] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-3- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0522] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2-methylpyrimidin-4-yl) benzamide
[0523] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) picolinamide
[0524] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-5- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0525] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrimidin-4-yl) benzamide
[0526] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (imidazo [1,2-a] pyrimidin-6-yl) benzamide
[0527] (R) -N- (1-cyanopyrrolidin-3-yl) -2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0528] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) nicotinamide
[0529] (R) -N- (1-cyanopyrrolidin-3-yl) -3,5-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0530] (R) -N- (1-cyanopyrrolidin-3-yl) -2,6-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0531] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carboxamide (R) -N - (1-cyanopyrrolidin-3-yl) -2-fluoro-3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamide (R) -6- (3-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-2-carboxamide
[0532] (R) -6- (4-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-2-carboxamide
[0533] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (imidazo [1,2-a] pyridin-6-yl) benzamide
[0534] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2-morpholinopyridin-4-yl) benzamide
[0535] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (1-methyl-1 H-indazol-5-yl) picolinamide
[0536] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (1-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) picolinamide (R) -N - (1-cyanopyrrolidin-3-yl) -5- (1,3-dimethyl-1 H-pyrazol-4-yl) -3-fluoroopicolinamide
[0537] (R) -3-chloro-N- (1-cyanopyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide
[0538] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide (R) -N - (1-cyanopyrrolidin-3-yl) -6- (1,3-dimethyl-1 H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide (R) -N- (1 -cyanopyrrolidin-3-yl) -5- (1-methyl-1 H-pyrazol-4-yl) -1 H-indazole-3-carboxamide
[0539] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1 H-pyrazol-4-yl) -1 H-indazole-3-carboxamide
[0540] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -1 H-indole-2-carboxamide
[0541] (R) -N- (1 -cyanopyrrolidin-3-yl) -6- (1,3-dimethyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide (R) -N- ( 1-cyanopyrrolidin-3-yl) -5- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide
[0542] (R) -N- (1-cyanopyrrolidin-3-yl) -2,3-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0543] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-ethyl-1 H-pyrazol-4-yl) -4-methylpicolinamide
[0544] (R) -N- (1-cyanopyrrolidin-3-yl) -3-phenoxyazetidin-1-carboxamide
[0545] (R) -3- (1 H-benzo [d] imidazol-2-yl) -N- (1-cyanopyrrolidin-3-yl) azetidin-1-carboxamide
[0546] (R) -N- (1-cyanopyrrolidin-3-yl) -4-phenylpiperazin-1-carboxamide
[0547] N - ((R) -1-cyanopyrrolidin-3-yl) -2-phenylmorpholine-4-carboxamide
[0548] (R) -4- (2-chloro-6-fluorobenzyl) -N- (1-cyanopyrrolidin-3-yl) -1,4-diazepane-1-carboxamide (R) -4-benzyl-N- (1 - cyanopyrrolidin-3-yl) -1,4-diazepane-1-carboxamide
[0549] (R) -N- (1-cyanopyrrolidin-3-yl) -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indole-2-carboxamide N - ((R) -1- cyanopyrrolidin-3-yl) -2 - ((2S, 6R) -2,6-dimethylmorpholino) -5-fluoroisonicotinamide (R) -N- (1-cyanopyrrolidin-3-yl) -5-fluoro-2- (isoindolin -2-yl) isonicotinamide
[0550] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4- (pyrimidin-2-ylamino) benzamide
[0551] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrrolidin-1-yl) benzamide
[0552] (R) -N- (1-cyanopyrrolidin-3-yl) -2,5-difluoro-4-morpholinobenzamide
[0553] (R) -N- (1-cyanopyrrolidin-3-yl) -2,5-difluoro-4- (pyrrolidin-1-yl) benzamide
[0554] N - ((R) -1-cyanopyrrolidin-3-yl) -2-fluoro-4 - ((R) -3-methoxypyrrolidin-1-yl) benzamide
[0555] (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (pyrimidin-2-ylamino) benzamide (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4 - ((4-methylpyrimidin-2-yl) amino) benzamide
[0556] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4 - ((4-methoxypyrimidin-2-yl) amino) benzamide
[0557] N - ((R) -1-cyanopyrrolidin-3-yl) -5-methyl-1 - (1-phenylethyl) -1 H-pyrazole-3-carboxamide
[0558] (R) -N- (1-cyanopyrrolidin-3-yl) -5-methyl-1 - (pyridin-2-ylmethyl) -1 H-pyrazole-3-carboxamide
[0559] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyridazin-4-yl) benzamide
[0560] (R) -N- (1-cyanopyrrolidin-3-yl) -1 -isobutyl-6- (1-methyl-1 H-pyrazol-4-yl) -1 H-indazole-3-carboxamide
[0561] (R) -N- (1 -cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -1 -isobutyl-1 H-indazole-3-carboxamide (R) -N- (1 -cyanopyrrolidin-3-yl) -1- (cyclopropylmethyl) -6- (3,5-dimethylisoxazol-4-yl) -1 H-indazole-3-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl ) -N-methyl-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide
[0562] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -N-methyl-1H-benzo [d] imidazole-2-carboxamide (R) - N- (1-cyanopyrrolidin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-3-carboxamide
[0563] (R) -7- (3-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-3-carboxamide
[0564] (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-7- (2-methylpyridin-4-yl) imidazo [1,2-a] pyridine-3-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-7- (6-methylpyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxamide (R) -N- (1-cyanopyrrolidin-3 -yl) -7- (1,3-dimethyl-1 H-pyrazol-4-yl) -N-methylimidazo [1,2-a] pyridine-3-carboxamide (R) -N- (1-cyanopyrrolidin-3 -yl) -7- (2,6-dimethylpyridin-4-yl) -N-methylimidazo [1,2-a] pyridine-3-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl) -N -ethyl-7- (2-methylpyridin-4-yl) imidazo [1,2-a] pyridine-3-carboxamide
[0565] (R) -N- (1-cyanopyrrolidin-3-yl) -7-morpholinoimidazo [1,2-a] pyridine-3-carboxamide
[0566] (R) -6- (3-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide
[0567] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide ( R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1,3-dimethyl-1H-pyrazol-4-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide (R) -N- (1 -cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrazolo [1,5-a] pyrimidin-5-yl) benzamide
[0568] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide
[0569] N - ((2R, 3R) -1-cyano-2-methylpyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide
[0570] 3-chloro-N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -4-morpholinobenzamide
[0571] N - ((3R, 4R) -1-cyano-4-fluoropyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide
[0572] N - ((3R, 4R) -1 -cyano-4-cyclopropylpyrrolidin-3-yl) -3-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0573] N - ((3S, 4S) -1 -cyano-4-methoxypyrrolidin-3-yl) -N-methyl-4- (1-methyl-1 H-pyrazol-4-yl) benzamide
[0574] (R) -N- (1-cyanopyrrolidin-3-yl) -5- (1,3-dimethyl-1H-pyrazol-4-yl) picolinamide
[0575] (R) -N- (1 -cyanopyrrolidin-3-yl) -5- (2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) picolinam ida
[0576] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (2,6-dimethylpyrimidin-4-yl) -2-fluorobenzamide
[0577] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (5-fluoro-2-methylpyrimidin-4-yl) benzamide
[0578] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2- (trifluoromethyl) pyrimidin-4-yl) benzam ida
[0579] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2-methyl-3H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (imidazo [1,2-a] pyrazin-3-yl) benzamide
[0580] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (pyrazolo [1,5-a] pyrimidin-5-yl) picolinamide
[0581] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (imidazo [1,2-a] pyridin-6-yl) picolinamide
[0582] (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-3-phenylazetidine-1-carboxamide
[0583] (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-3-phenylazetidine-1-carboxamide
[0584] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (4-methoxyphenyl) azetidine-1-carboxamide
[0585] (R) -3- (4-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide
[0586] (R) -3- (3-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide
[0587] (3aR, 6aR) -1 - (3-phenylazetidin-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile
[0588] (R) -1 - (1 -cyanopyrrolidin-3-yl) -1-methyl-3- (4- (1-methyl-1 H-pyrazol-4-yl) phenyl) urea
[0589] (R) -1 - (1 -cyanopyrrolidin-3-yl) -1 -methyl-3- (4- (trifluoromethyl) phenyl) urea
[0590] (3aR, 6aR) -N- (4-chloro-2-fluorophenyl) -5-cyanohexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (2 -fluoro-4- (trifluoromethoxy) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (4-cyano-2-fluorophenyl) hexahydropyrrolo [3 , 4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (4-cyano-2,5-difluorophenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -N- (5-chloro-2-fluorophenyl) -5-cyanohexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (2-fluoro-5- (trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (5-phenylpyridin-2-yl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide
[0591] (3aR, 6aR) -5-cyano-N- (4- (trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide
[0592] (R) -1 - (1 -cyanopyrrolidin-3-yl) -1 -ethyl-3- (4- (trifluoromethyl) phenyl) urea
[0593] 1 - (1 -cyanopyrrolidin-3-yl) -1 - (2-methoxyethyl) -3- (4- (trifluoromethyl) phenyl) urea
[0594] (R) -N- (1-cyanopyrrolidin-3-yl) -N-ethyl-3-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide
[0595] (R) -N- (1-cyanopyrrolidin-3-yl) -N-ethyl-3-phenylazetidine-1-carboxamide
[0596] (R) -3- (2-oxo-3- (4-phenylthiazol-2-yl) imidazolidin-1-yl) pyrrolidin-1-carbonitrile
[0597] (R) -3- (2-oxo-3- (4-phenylthiazol-2-yl) tetrahydropyrimidin-1 (2H) -yl) pyrrolidin-1-carbonitrile
[0598] (R) -3- (3- (3-morpholinophenyl) -2-oxoimidazolidin-1-yl) pyrrolidin-1-carbonitrile
[0599] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (pyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxamide
[0600] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (4-cyclopropylpyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxamide (R) -N- (1-cyanopyrrolidin-3-yl) -4 - ((4-cyclopropylpyrimidin-2-yl) amino) -3-fluorobenzamide
[0601] (R) -N- (1-cyanopyrrolidin-3-yl) -4 - ((4-cyclopropylpyrimidin-2-yl) amino) -2,3-difluorobenzamide
[0602] (R) -N- (1-cyanopyrrolidin-3-yl) -4- (N-methylisobutyramido) picolinamide
[0603] (R) -N- (1-cyanopyrrolidin-3-yl) - [2,3'-bipyridine] -6'-carboxamide
[0604] (R) -N- (1-cyanopyrrolidin-3-yl) - [2,4'-bipyridine] -2'-carboxamide
[0605] (R) -3- (4-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) isoxazole-5-carboxamide
[0606] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (4- (trifluoromethyl) phenyl) isoxazole-5-carboxamide
[0607] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (3,4-dimethoxyphenyl) isoxazole-5-carboxamide
[0608] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (3-methoxyphenyl) isoxazole-5-carboxamide
[0609] N - ((R) -1 -cyanopyrrolidin-3-yl) -1-phenylpyrrolidine-3-carboxam ida
[0610] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4- (4-methyl-1 H-imidazol-1-yl) benzamide
[0611] (R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-N-methyl-4- (4-methyl-1 H-imidazol-1-yl) benzamide
[0612] N - ((R) -1 -cyanopyrrolidin-3-yl) -3- (pyridin-2-yl) pyrrolidin-1-carboxamide
[0613] N - ((R) -1 -cyanopyrrolidin-3-yl) -3- (1 -methyl-1H-pyrazol-4-yl) pyrrolidin-1-carboxamide
[0614] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (2-methoxypyridin-4-yl) -N-methylisoxazole-5-carboxamide
[0615] (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (N-methylphenylsulfonamido) benzamide
[0616] (R) -N- (1-cyanopyrrolidin-3-yl) -1-methyl-6- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide
[0617] (R) -N- (1-cyanopyrrolidin-3-yl) -1-methyl-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide
[0618] (R) -1 - (1 -cyanopyrrolidin-3-yl) -3- (2- (isoindolin-2-yl) pyridin-4-yl) -1-methylurea
[0619] (R) -N- (1-cyanopyrrolidin-3-yl) -3-f luoro-1-methyl-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide
[0620] (R) -N- (1-cyanopyrrolidin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a] pyridine-3-carboxamide
[0621] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (1-phenyl-1 H-pyrazol-3-yl) azetidine-1-carboxamide
[0622] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (1 - (pyrazin-2-yl) -1 H-pyrazol-3-yl) azetidin-1-carboxamide
[0623] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (2-phenylpyrimidin-4-yl) azetidin-1-carboxam ida
[0624] (R) -3- (2- (4-chlorophenyl) pyrimidin-4-yl) -N- (1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide
[0625] (R) -3- (benzyloxy) -N- (1-cyanopyrrolidin-3-yl) -3-phenylazetidine-1-carboxamide
[0626] (R) -N- (1-cyanopyrrolidin-3-yl) -1- (4-cyclopropylpyrimidin-2-yl) indoline-5-carboxamide
[0627] (R) -N- (1-cyanopyrrolidin-3-yl) -1- (4-cyclopropylpyrimidin-2-yl) -N-methylindoline-5-carboxamide
[0628] (3aR, 6aR) -5-cyano-N- (3- (2-methylpyridin-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5- Cyano-N- (4- (2-methylpyridin-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (2-fluoro -4- (2-methylpyridin-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (2'-methyl- [3 , 4'-bipyridin] -6-yl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide (3aR, 6aR) -5-cyano-N- (2-fluoro-4- (1-methyl -1 H-pyrazol-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrolo-1 (2H) -carboxamide 1 - (3-phenyl-1 H-pyrazole-5-carbonyl) hexahydropyrrolo [3,4- b] pyrrolo-5 (1 H) -carbonitrile
[0629] (3aR, 6aR) -1 - (3-phenoxyazetidin-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile
[0630] N- (1-cyanopiperidin-3-yl) - [1,1'-biphenyl] -3-carboxamide
[0631] 1 - (3-benzylphenyl) -3- (1-cyanopiperidin-3-yl) urea
[0632] 1 - (1-cyanopiperidin-3-yl) -3- (3-phenoxyphenyl) urea
[0633] 1 - (1-cyanopyrrolidin-3-yl) -3- (2,4-dichlorophenyl) urea
[0634] 1 - (1-cyanopyrrolidin-3-yl) -3- (4- (trifluoromethyl) phenyl) urea
[0635] 1 - (3-benzylphenyl) -3- (1-cyanopyrrolidin-3-yl) urea
[0636] 1 - ([1,1'-biphenyl] -4-yl) -3- (1-cyanopyrrolidin-3-yl) urea
[0637] 1 - (1-cyanopyrrolidin-3-yl) -3- (3-phenoxyphenyl) urea
[0638] 3- (3-benzylphenyl) -1 - (1 -cyanopyrrolidin-3-yl) -1-methylurea
[0639] 3- (3-chlorophenyl) -1 - (1-cyanopyrrolidin-3-yl) -1-methylurea
[0640] 1 - (1 -cyanopyrrolidin-3-yl) -1-methyl-3- (3-phenoxyphenyl) urea
[0641] 3 - ([1,1'-biphenyl] -4-yl) -1 - (1 -cyanopyrrolidin-3-yl) -1-methylurea
[0642] 1 - (1-cyanopyrrolidin-3-yl) -3- (2,4-dichlorophenyl) -1-methylurea
[0643] 1 - (1-cyanopyrrolidin-3-yl) -1-methyl-3- (4- (trifluoromethyl) phenyl) urea
[0644] (R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -N-methyl-1 H-indole-2-carboxamide
[0645] (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-pyrrolo [2,3-c] pyridin- 2-carboxamide
[0646] N - ((R) -1-cyanopyrrolidin-3-yl) -N-methyl-2-phenylmorpholine-4-carboxamide
[0647] (R) -N- (1-cyanopyrrolidin-3-yl) -N-methylindolin-1-carboxamide
[0648] (R) -1 - (1 -cyanopyrrolidin-3-yl) -1 -methyl-3- (6- (trifluoromethyl) pyridin-3-yl) urea
[0649] (R) -3- (5-chloropyridin-2-yl) -1 - (1-cyanopyrrolidin-3-yl) -1-methylurea
[0650] (3aR, 6aR) -1- (3-chloro-4-morpholinobenzoyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile
[0651] (3aR, 6aR) -1 - (indolin-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrolo-5 (1 H) -carbonitrile
[0652] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) isoxazole-5-carboxamide
[0653] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (3,4-dimethylphenyl) isoxazole-5-carboxamide
[0654] (R) -N- (1-cyanopyrrolidin-3-yl) -3- (2,4-difluorophenyl) isoxazole-5-carboxamide
[0655] (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-3- (2-methylpyridin-4-yl) isoxazole-5-carboxamide
[0656] It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.
[0657] Described herein is 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 (IV) with a compound R12-Y-COOH to form an amide:
[0661] Where R1, R2, R3, R8, R9, R10, X and n are as defined elsewhere and PG is an amine protecting group. The protecting group can be, but is not limited to, BOC. Combining or adjusting such a chemical protecting group is obvious to one skilled in the art. After the coupling of R12-Y-COOH to form an amide, the protecting group can be removed to leave the free amine according to formula (V) which can then be treated with cyanogen bromide to form compounds according to formula (I) .
[0662] Also described is 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 (V) with cyanogen bromide to form N-CN compounds:
[0663] According to a further aspect of the disclosure, there is provided a process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof comprising the steps of reacting an amine of formula (IVA) with a compound R12-Y -COOH to form an amide:
[0668] Where R1, R2, R3, R4, R5, R8, R9, R10, R12, Z and m are as defined elsewhere for formula II and PG is an amine protecting group. The protecting group can be, but is not limited to, BOC. Combining or adjusting such a chemical protecting group is obvious to one skilled in the art. After the coupling of R12-Y-COOH to form an amide, the protecting group can be removed to leave the free amine according to formula (VA) which can then be treated with cyanogen bromide to form compounds according to formula (II) .
[0670] According to a further aspect of the disclosure, there is provided a process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof comprising the steps of reacting an amine of formula (VA) with cyanogen bromide to form N-CN compounds:
[0675] Where R1, R2, R3, R4, R5, R8, R9, R10, Z and m are as defined elsewhere for formula II.
[0677] According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (II).
[0679] The pharmaceutical compositions of this invention comprise any of the compounds of the invention in combination with any pharmaceutically acceptable carrier, adjuvant, or vehicle. Examples of pharmaceutically acceptable carriers are known to those skilled in the art and include, but are not limited to, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions can be in the form of, for example, tablets, capsules, powders, granules, elixirs, lozenges, suppositories, syrups, and liquid preparations including suspensions and solutions. The term "pharmaceutical composition" in the context of this invention means a composition comprising an active agent and additionally comprising one or more pharmaceutically acceptable carriers. The composition may additionally contain ingredients selected from, for example, diluents, adjuvants, excipients, carriers, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms.
[0681] According to a further aspect of the invention, there is provided a compound of formula (II) or a pharmaceutical composition thereof for use in therapy.
[0683] Also disclosed is a compound of formula (IA) or a pharmaceutical composition thereof for use in the treatment of cancer and conditions involving mitochondrial dysfunction.
[0685] or one of its pharmaceutically acceptable salts, where:
[0686] n is 1 or 2;
[0687] when n is 1, X is CR4R5 and when n is 2, X is CR6R7CR4R5 (where CR4R5 is adjacent to the N atom of the heterocycle);
[0688] R2 represents a hydrogen atom, cyano, an ^{optionally substituted C 1} -C ⁶ alkyl, an optionally substituted C ¹ -C ⁶ alkoxy group, a heteroaryl, heterocyclyl, 4 to 10 membered aryl or 3 to 8 membered cycloalkyl ring optionally substituted;
[0689] R1, R3, R4 and R5 each independently represent a hydrogen atom, cyano, a C ¹ -C ³ alkoxy or optionally substituted C ¹ -C ³ alkyl group optionally substituted;
[0690] R6, R7 and R8 each independently represent a hydrogen atom, a fluorine atom, cyano, an alkyl group C ¹ -C ³ alkoxy or optionally substituted C ¹ -C ³ optionally substituted;
[0691] R9 represents a hydrogen atom, a fluorine atom, cyano, an ^{optionally substituted C 1} -C ⁶ alkyl, an optionally substituted C ¹ -C ³ alkoxy group, a heteroaryl, heterocyclyl, 4 to 10 membered aryl or cycloalkyl ring 3- to 8-membered optionally substituted, or forms an optionally substituted heterocyclic ring with R10 wherein the ring optionally comprises one or more additional heteroatoms;
[0692] R10 represents a hydrogen atom, C ¹ -C ⁶ alkyl, or forms a heterocyclic ring optionally substituted with R9 or R11 wherein the ring optionally comprises one or more additional heteroatoms;
[0693] Y represents a covalent bond, NR11 or optionally substituted ^{C 1} -C ^{3 alkylene;}
[0694] R11 represents a hydrogen atom, an ^{optionally substituted C 1} -C ⁶ alkyl, a heteroaryl, heterocyclyl, 4 to 10 membered aryl or 3 to 8 membered cycloalkyl ring, or forms an optionally substituted heterocyclic ring with R10 wherein the ring optionally comprises one or more additional heteroatoms;
[0695] R12 represents an optionally substituted 3- to 8-membered heteroaryl, heterocyclyl, aryl or 3- to 8-membered cycloalkyl ring.
[0696] Additional definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and Y include those described in the above embodiments for formulas (I), (IB), and (IID) .
[0697] Conditions involving mitochondrial dysfunction
[0698] The compounds of the invention according to formulas (I), (IA) and (II) can be used in the treatment of disorders or diseases having a component related to mitochondrial dysfunction, in particular disorders or diseases linked to the activity of DUB. More particularly, disorders or diseases are related to the activity of USP30.
[0699] The compounds of formulas (I), (IA) and (II) as described herein can be used in the manufacture of a medicament for the treatment of conditions involving mitochondrial dysfunction.
[0700] In a further aspect of the disclosure, there is provided a method of treating or preventing a condition involving mitochondrial dysfunction, the method comprising administering a pharmaceutically effective amount of a compound of formulas (I), (IA) and (II) or a pharmaceutical composition thereof to an individual diagnosed with a condition involving mitochondrial dysfunction.
[0701] Mitochondrial dysfunctions are the result of defects in the mitochondria, which are specialized compartments present in all cells of the body except red blood cells. When mitochondria fail, less and less energy is generated within the cell and cell injury or even cell death will occur. If this procedure is repeated throughout the body, the life of the subject where this occurs is seriously compromised. Diseases of the mitochondria appear more frequently in organs that require lots of energy, such as the brain, heart, liver, skeletal muscles, kidneys, and the endocrine and respiratory systems.
[0703] The condition that involves mitochondrial dysfunction can be selected from a condition that involves a mitophagy defect, a condition that involves a mutation in mitochondrial DNA, a condition that involves mitochondrial oxidative stress, a condition that involves a defect in membrane potential mitochondrial, mitochondrial biogenesis, a condition that involves a defect in mitochondrial shape or morphology, and a condition that involves a lysosomal storage defect.
[0705] In particular, the condition involving mitochondrial dysfunction can be selected from a neurodegenerative disease; mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS); Leber's hereditary optic neuropathy (LHON); Cancer; neuropathy, ataxia, retinitis pigmentosa-Leigh syndrome inherited from the mother (NARP-MILS); Danon disease; diabetes; metabolic disorders; ischemic heart disease leading to myocardial infarction; psychiatric illnesses, for example schizophrenia; multiple sulfatase deficiency (MSD); mucolipidosis II (ML II); mucolipidosis III (ML III); mucolipidosis IV (ML IV); gangliosidosis GM1 (GM1); neuronal ceroid lipofuscinosis (NCL1); Alpers disease; Barth syndrome; beta oxidation defects; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndromes; Coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; 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; Kearns-Sayre syndrome; lactic acidosis; long chain acyl-CoA dehydrogenase deficiency (LCHAD); Leigh's disease or syndrome; infantile fatal cardiomyopathy (SCI); Luft's disease; glutaric aciduria type II; medium chain acyl-CoA dehydrogenase deficiency (MCAD); myoclonic epilepsy and irregular red fiber syndrome (MERRF); mitochondrial cytopathy; recessive mitochondrial ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastointestinal disorder and encephalopathy; Pearson's syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium / short chain 3-hydroxyacyl-CoA dehydrogenase deficiency (M / SCHAD); and very long chain acyl-CoA dehydrogenase deficiency (VLCAD).
[0707] The condition involving mitochondrial dysfunction can be a CNS disorder, for example a neurodegenerative disease.
[0709] Neurodegenerative diseases include, but are not limited to, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, ischemia, stroke, Lewy body dementia, and frontotemporal dementia.
[0711] In a particular embodiment, the compounds of the invention are useful in the treatment of Parkinson's disease, including, but not limited to, PD related to mutations in α-synuclein, parkin and PINK1, autosomal recessive juvenile Parkinson's disease (RA -JP) where parkin is mutated.
[0713] The compounds of formulas (I), (IA) and (II) or the pharmaceutical compositions thereof as described herein may be combined with one or more additional agents when used for the treatment of conditions involving mitochondrial dysfunction. . The compounds can be combined with one or more additional agents selected from levodopa, a dopamine agonist, a monoaminooxygenase (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 anticonvulsant.
[0715] Cancer
[0717] The compounds of formulas (I) and (IA) also have use in the treatment of cancer and more particularly in the treatment of cancer related to the activity of DUB, especially the activity of USP30.
[0719] The compounds of the invention according to formula (II) also have use in the treatment of cancer and more specifically in the treatment of cancer linked to DUB activity or deumoylation activity. Compounds of the invention may be useful against any DUB or deumoylating enzyme, including, but not limited to USP30 and USP10.
[0721] The compounds described herein can be used in the manufacture of a medicament for the treatment of cancer linked to the activity of DUB.
[0723] The compounds of formulas (I), (IB) and (II) as described herein can also be used in the manufacture of a medicament for the treatment of cancer. In a further aspect of the disclosure, a method of treating or preventing a cancer is provided, the method comprising administering a pharmaceutically effective amount of a compound of formulas (I), (IB) and (II) or a pharmaceutical composition thereof. to an individual suffering from cancer.
[0725] The compounds of the invention also have use in the treatment of cancer related to mitochondrial dysfunction.
[0726] In one embodiment, the compounds according to the invention have use in the treatment of cancer when the apoptotic pathways are deregulated and more specifically when the proteins of the BCL-2 family are mutated, or overexpressed or insufficiently expressed.
[0728] References to "cancer" or "tumor" include, but are not limited to, breast, ovarian, prostate, lung, kidney, stomach, colon, testicular, head and neck, pancreas, brain, melanoma, bone, or other cancers. tissue and organ and blood cell cancers such as lymphomas and leukemias. Particular cancers include lymphoma, multiple myeloma, colorectal cancer, and non-small cell lung carcinoma.
[0730] The compounds of formulas (I), (IA) and (II) 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 can be combined with an additional antitumor therapeutic agent, eg, chemotherapeutic drugs or inhibitors of other regulatory proteins. In one embodiment, the additional antitumor therapeutic agent is a BH-3 mimetic. In a further embodiment, the BH-3 mimetics may be selected from, but not limited to, one or more of ABT-737, ABT-199, ABT-263 and Obatoclax. In a further embodiment, the additional antitumor agent is a chemotherapeutic agent. Chemotherapeutic agents can be selected from, but not limited to, olaparib, mitomycin C, cisplatin, carboplatin, oxaliplatin, ionizing radiation (IR), camptothecin, irinotecan, topotecan, temozolomide, taxanes, 5-fluoropyrimidines, gemcitabine, and doxorubicin.
[0732] To treat a mitochondrial dysfunction disorder, the pharmaceutical compositions of the invention can be designed for oral, parenteral or mucosal administration and the choice or specific form of composition depends on the route of administration. Thus, for oral administration, the composition may be in the form, for example, of tablets, lozenges, lozenges, films, powders, elixirs, syrups, liquid preparations including dispersions, suspensions, emulsions, solutions or aerosols, cachets, granules, capsules, etc. For administration to the mucosa, the composition may be in the form of aerosols, 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 that includes liposome compositions.
[0734] To treat a CNS disorder, the compounds of the invention must have the ability to cross the blood-brain barrier. As such, such compounds have the ability to enter a patient's central nervous system. Alternatively, the pharmaceutical compositions of the present invention can bypass the blood brain barrier using compositions and methods known in the art to bypass the blood brain barrier or can be injected directly into the brain. Suitable sites for injection include the cerebral cortex, cerebellum, midbrain, brainstem, hypothalamus, spinal cord, and ventricular tissue, and areas of the PNS including the carotid body and adrenal medulla. Other dosage forms include those suitable for oral administration including, but not limited to, tablets, lozenges, powders, elixirs, syrups, liquid preparations including suspensions, aerosols, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, and capsules. For parenteral administration, preparations include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions.
[0736] To treat cancer, the pharmaceutical compositions of the invention may be administered in any effective manner suitable to target cancer cells, for example, orally in any orally acceptable dosage form, including, but not limited to, tablets. , dragees, powders, elixirs, syrups, liquids. preparations including suspensions, aerosols, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, and capsules. Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions.
[0738] Such dosage forms are prepared according to techniques known in the art of pharmaceutical formulation. When in the form of aerosols or inhalants, the pharmaceutical compositions can be administered nasally. Formulations suitable for this purpose are known to those skilled in the art.
[0740] The pharmaceutical compositions of the invention can be administered by injection and can be in the form of a sterile liquid preparation for injection, including liposome preparations.
[0742] The pharmaceutical compositions of the invention may also be in the form of suppositories for rectal administration. These are formulated so that the pharmaceutical composition is solid at room temperature and liquid at body temperature to allow release of the active compound.
[0744] Dosages can be varied depending on the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the appropriate dose for a particular situation is within the competence of one of ordinary skill in the art. Treatment generally begins with smaller doses that are less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved under the circumstances.
[0746] The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. Selection of appropriate dosages is within the ability of one of ordinary skill in the art, without undue burden. The interval of Daily dose is from about 10 pg to about 100 mg per kg of body weight of a human and non-human animal and, in general, it can be from about 10 pg to 30 mg per kg of body weight per dose. The above dose can be administered one to three times a day.
[0747] Synthetic methodologies
[0748] Compounds of the invention can be prepared by a variety of synthetic routes. Illustrative routes for certain compounds of the invention are shown below. Representative compounds of the present invention can be synthesized according to the general synthetic methods described below and are more specifically illustrated in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions stated. The preparation of the various starting materials used in the schemes is well within the knowledge of those of ordinary skill in the art. Those skilled in the art will appreciate that, where appropriate, individual transformations within a scheme can be completed in a different order. The following schemes describe general synthetic methods by which intermediates and targets of the present invention can be prepared. Additional representative compounds and stereoisomers, racemic mixtures, diastereomers and enantiomers thereof can be synthesized using the intermediates prepared according to the general schemes and other materials, compounds and reagents known to those of skill in the art. All such compounds, stereoisomers, racemic mixtures, diastereomers and enantiomers thereof are intended to be included within the scope of the present invention.
[0749] The compounds were characterized by liquid chromatography-mass spectroscopy (LCMS) and / or NMR 1 H Abbreviations:
[0750] Aqueous harassment
[0751] Ar Arilo
[0752] BOC Tert-butyloxycarbonyl
[0753] br Width (NMR signal)
[0754] d Doublet (NMR signal)
[0755] CDI Carbonyldiimidazole
[0756] DCM Dichloromethane
[0757] DCE 1,2-Dichloroethane
[0758] DIPEA Diisopropylethylamine
[0759] DMA Dimethylacetamide
[0760] DMAP Dimethylaminopyridine
[0761] DMF N, N-dimethylformamide
[0762] DMSO Dimethylsulfoxide
[0763] dppf 1,1'-Bis (diphenylphosphino) ferrocene
[0764] EDC 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
[0765] ES Electrospray
[0766] EtOAc Ethyl acetate
[0767] EtOH Ethanol
[0768] Fmoc Fluorenylmethyloxycarbonyl
[0769] h Hour or hours
[0770] HATU 1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide 1- [bis (dimethylamino) methylene] hexafluorophosphate] HBTU O-benzotriazole-N, N, N ', N' hexafluorophosphate -tetramethyl-uronium
[0771] HOAt 1 -Hydroxy-7-azabenzotriazole
[0772] HOBT 1-Hydroxybenzotriazole
[0773] IPA Isopropyl Alcohol
[0774] LDA Lithium Diisopropylamide
[0775] LiHMDS Lithium hexamethyldisilazide
[0776] m Multiplete (NMR signal)
[0777] MeCN Acetonitrile
[0778] MeOH Methanol
[0779] min Minutes)
[0780] NCS N-chlorosuccinimide
[0781] PE Petroleum ether
[0782] rt Ambient temperature
[0783] RT Retention time
[0784] s Singlet (NMR signal)
[0785] t Triplet (NMR signal)
[0786] T3P 2,4,6-T ripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBAI Tetrabutylammonium iodide
[0787] TBD 1,5,7-Triazabicyclo [4,4,0] dec-5-ene
[0788] TEA Triethylamine
[0789] TFAA Trifluoroacetic anhydride
[0790] TFA Trifluoroacetic acid
[0791] THF Tetrahydrofuran
[0792] TLC Thin Layer Chromatography
[0793] Xantphos 4,5-Bis (diphenylphosphino) -9,9-dimethylxanthene
[0794] X-Phos 2-Dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl Analytical methods:
[0796]
[0797]
[0798]
[0799]
[0800]
[0801]
[0802]
[0803]
[0804]
[0805]
[0806]
[0807]
[0808]
[0809]
[0810]
[0811] General method A
[0813]
[0815] Reagents and conditions: a) EDC.HCl, HOBT, DIPEA, THF, rt, 15 h; b) TFA, DCM, 0 ° C and then at 50 ° C, 12 h; c) Cyanogen bromide, K ² CO ³ , THF, 0 ° C then at rt, 30 min
[0816] General method B
[0818]
[0820] Reagents and conditions: a) Pd (PPh3) 4, Na2CO3, 1,4-dioxane: water (2: 1), 90 ° C, 8 h; b) UOH.H ² O, THF, water (1: 1), rt, 3 h; c) HATU, DIPEA, THF, 0 ° C and then at rt, 2 h; d) TFA, DCM, 0 ° C and then at rt, 2 h; e) cyanogen bromide, K ² CO ³ , THF, 0 ° C then at rt, 1 h
[0821] General method C
[0823]
[0825] Reagents and conditions: a) T3P (50% in EtOAc), DIPEA, THF, 0 ° C and then at rt, 1.5 h; b) ArB (OH) ² , Pd (PPh3) 4, K ² CO ³ , 1,4-dioxane: water (5: 1), 80 ° C, 2 h; c) TFA, DCM, 0 ° C and then at rt, 2 h; d) Cyanogen bromide, K2CO3, THF, 0 ° C then at rt, 20 min
[0826] General method D
[0828]
[0830] Reagents and conditions: a) HATU, DIPEA, DCM, 0 ° C then rt, 16 h; b) R ¹ R ² NH, CS ² CO ³ , DMF, 120 ° C, 16 h; c) HCl / EtOAc, rt, 2 h; d) cyanogen bromide, NaHCO3, EtOH, rt, 16 h
[0831] General method E
[0833]
[0835] Reagents and conditions: a) CDI, water, (or THF or DCM), 0 ° C, 30 min and then rt, 18 h (or triphosgene, TEA, DCM, 0 ° C); b) TFA, DCM, rt, 3 h; c) Cyanogen bromide, DIPEA, DCM, 0 ° C, 30 min
[0836] General method F
[0838]
[0840] Reagents and conditions: a) (optionally substituted) cis-2,6-dimethylmorpholine, NaOtBu, Xantphos, Pd2 (dba) 3, toluene, 110 ° C, 1 hr; b) LiOH.H ² O, THF, water, 50 ° C 4 h, then at rt, 15 h; c) HATU, DIPEA, DMF, rt, 2 h; d) TFA, DCM, rt, 1 hr; e) cyanogen bromide, K ² CO ³ , THF, rt, 30 min
[0841] General method G
[0843]
[0845] Reagents and conditions: a) HATU, DIPEA, THF, rt, 4 h; b) NaOtBu, DBU, BINAP, Pd2 (dba) 3, toluene, 110 ° C, 1 hr; c) TFA, DCM, rt 1 hr; d) cyanogen bromide, K ² CO ³ , THF, rt, 30 min
[0846] General method H
[0848]
[0850] Reagents and conditions: a) HATU, DIPEA, THF, rt, 4 h; b) R ¹ R ² NH, NaOtBu or Cs2CO3, BINAP or Xantphos, Pd2 (dba) 3, toluene or dioxane: water, 110 ° C, 1 h; c) TFA, DCM, rt 1 hr; d) cyanogen bromide, K ² CO ³ , THF, rt, 30 min Example 1 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -5-phenylpicolinamide
[0851] (Prepared according to general method A)
[0853]
[0855] Stage a. To a solution of (R) -3-amino-1N-BOC-pyrrolidine (0.24 mmol) in THF (10 ml) was added EDC.HCl (0.33 mmol), HOBt (0.33 mmol) and DIPEA (0.45 mmol) at rt. The reaction mixture was stirred at rt for 15 min. 5-Phenylpyridine-2-carboxylic acid (0.22mmol) was added to the reaction mixture at rt and stirred for 15h. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 10 ml). The combined organic phase was collected, dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure yielding tert-butyl (R) -3- (5-phenylpicolinamido) pyrrolidine-1-carboxylate (quantitative). This substance was used directly for the next step without further purification. MS: ES + 312.2 (M-tBu).
[0856] Stage b. To a solution of tert-butyl (R) -3- (5-phenylpicolinamido) pyrrolidine-1-carboxylate (0.27 mmol) in DCM (10 ml) was added TFA (1 ml) at 0 ° C. The reaction mixture was stirred at rt for 3 hr and then heated at 50 ° C for 12 hr. The resulting reaction mixture was concentrated under reduced pressure. The residue obtained was azeotropically distilled using DCM (2 x 10 ml) and dried under reduced pressure yielding the TFA salt of (R) -5-phenyl-N- (pyrrolidin-3-yl) picolinamide (quantitative). This substance was used directly for the next step without further purification. MS: ES + 268.2
[0857] Stage c. To a TFA salt solution of (R) -5-phenyl-N- (pyrrolidin-3-yl) picolinamide (0.26 mmol) in THF (15 ml) was added K ² CO ³ (1.3 mmol ) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. Cyanogen bromide (0.31 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was then stirred at rt for 30 min. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 10 ml). The combined organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (40% EtOAc in hexane) yielding the title compound (0.11 mmol). LCMS: Method B, RT 3.68 min, MS: ES + 293.5; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.05 (d, J = 7.2 Hz, 1H), 8.95 -8.96 (m, 1H), 8.29 (dd, J = 1.2.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81 (dd, J = 1.6, 6.8 Hz, 2H), 7.55-7.57 (m, 2H), 7.47-7.50 (m, 1H), 4.53-4.58 (m, 1H), 3.55-3.65 ( m, 2H), 3.40-3.49 (m, 2H), 2.12-2.15 (m, 1H), 2.05-2.10 (m, 1H)
[0858] Example 2 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-methoxy-4- ( 1-methyl-1H-pyrazol-4-yl) benzamide
[0859] (Prepared according to general method B)
[0861]
[0863] Stage a. To a solution of methyl 4-bromo-3-methoxybenzoate (1.02 mmol) was added 1-methylpyrazole-4-boronic acid pinacol ester (1.52 mmol) in 1,4-dioxane: water ( 2: 1) (6 mL) Na2CO3 (3.35 mmol) at rt. The reaction mixture was purged with nitrogen for 10 min. Pd (PPh3) 4 (0.04 mmol) was added to the reaction mixture. The reaction mixture was heated at 90 ° C for 8 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure yielding methyl 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzoate (quantitative). This substance was used for the next step without further purification. MS: ES + 247.1
[0865] Stage b. To a solution of 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzoate (3.65 mmol) in THF: water (1: 1, 10 ml) was added LiOH.H ² Or (14.60 mmol) in portions at rt. The reaction mixture was stirred at rt for 3 h. The resulting mixture was poured into water (50 ml) and extracted with EtOAc (2 x 50 ml). The resulting aqueous layer containing the product was cooled to 0 ° C and neutralized by the slow addition of a dilute aqueous HCl solution. The resulting mixture was extracted with EtOAc (2 x 50 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzoic acid (1.63 mmol). MS: ES + 233.2
[0866] Stage c. To a solution of (R) -3-amino-1N-BOC-pyrrolidine (0.86 mmol) and 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzoic acid (0.86 mmol ) in THF (7 ml) were added HATU (1.29 mmol) and DIPEA (2.5 mmol) at 0 ° C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was collected and washed with a dilute citric acid solution (2 x 50 ml), brine (1 x 100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure yielding (R) -3 Tert-Butyl - (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamido) -pyrrolidine-1-carboxylate (0.9 mmol). MS: ES + 401.3
[0867] Stage d. To a solution of tert-butyl (R) -3- (3-methoxy-4- (1-methyl-1 H-pyrazol-4-yl) -benzamido) pyrrolidin-1-carboxylate (0.9 mmol) in DCM (10 ml) TFA (29.4 mmol) was added at 0 ° C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was azeotropically distilled with DCM (3 x 25 ml) and dried to yield (R) -3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) -N- TFA salt. (pyrrolidin-3-yl) benzamide (0.57 mmol). MS: ES + 301.24
[0869] Stage e. To a TFA salt solution of (R) -3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) -N- (pyrrolidin-3-yl) benzamide (0.57 mmol) in THF (10 ml) K ² CO ³ (4.7 mmol) and cyanogen bromide (0.79 mmol) were added at 0 ° C. The reaction mixture was stirred at rt for 1h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (1-5% MeOH in DCM) yielding (R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (1-methyl-1H-pyrazole- 4-yl) benzamide (0.29 mmol). LCMS: Method B, RT 2.97 min, MS: ES + 326.27; 1H NMR (400 MHz, DMSO-de) or ppm 8.56 (d, J = 6.4 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7 , 70 (d, J = 8.4 Hz, 1H), 7.48-7.50 (m, 2H), 4.45-4.53 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.63-3.67 (m, 1H), 3.54-3.60 (m, 1H), 3.43-3.49 ( m, 1H), 3.30-3.33 (m, 1H), 2.10-2.18 (m, 1H), 1.94-2.00 (m, 1H)
[0870] Example 3 2'-chloro-N- ( 1-cyanopyrrolid in-3-yl) - [1,1'-biphenyl] -4-carboxamide
[0872] (Prepared according to general method C)
[0874]
[0877] Stage a. To a solution of 4-bromobenzoic acid (4.97 mmol) in THF (20 ml) was added T3P (50% in EtOAc) (14.9 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 min. 3-Amino-1 N-BOC-pyrrolidine (5.93 mmol) and DIPEA (14.96 mmol) were added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 1.5 h. The resulting mixture was poured into a saturated NaHCO3 solution (80 ml) and extracted with EtOAc (2 x 40 ml). The organic layer was washed with M HCl (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by trituration using Et ² O: hexane (1: 1) yielding tert-butyl 3- (4-bromobenzamido) pyrrolidine-1-carboxylate (1.90 mmol). MS: ES + 369.13
[0879] Stage b. To a solution of tert-butyl 3- (4-bromobenzamido) pyrrolidine-1-carboxylate (0.67 mmol) and 2-chlorophenylboronic acid (1.01 mmol) in 1,4-dioxane: water (5: 1) (7.5 ml) K ² CO ³ (2.03 mmol) was added at rt. The reaction mixture was purged with nitrogen for 30 min. Pd (PPh3) 4 (0.03 mmol) was added to the reaction mixture under nitrogen atmosphere. The reaction was heated to 80 ° C for 2 h. The resulting mixture was poured into water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (0.5% MeOH in DCM) yielding tert-butyl 3- (2'-chloro- [1,1'-biphenyl] -4-carboxamido) pyrrolidine-1-carboxylate ( 0.5 mmol). MS: ES + 401.18, 1H NMR (400 MHz, DMSO-de) or ppm 8.65 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2 H), 7.65-7.58 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.44 (dd, J = 2.5.6 Hz, 2H ), 4.44-4.45 (m, 1H), 3.51-3.60 (m, 1H), 3.16-3.30 (m, 1H), 2.08-2.10 (m , 2H), 1.92-1.93 (m, 2H), 1.41 (s, 9H).
[0881] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 2. LCMS: Method B, RT 4.01 min, MS: ES + 326.23; 1H NMR (400 MHz, DMSO-d6) or ppm 8.70 (d, J = 6.4 Hz, 1H), 7.94 (d, J = 8.00 Hz, 2H), 7.59 - 7.62 (m, 1H), 7.54 (d, J = 8.00Hz, 2H), 7.42-7.46 (m, 3H), 4.49-4.53 (m , 1H), 3.60-3.68 (m, 1H), 3.54-3.58 (m, 1H), 3.45-3.56 (m, 1H), 3.34 - 3.44 (m, 1H), 2.01-2.17 (m, 1H), 1.95-2.01 (m, 1H)
[0882] Example 4 6- ( benzyl ( methyl) amino) -N- ( 1-cyanopyrrolidin-3-yl) nicotinamide
[0884] (Prepared according to general method D)
[0886]
[0889] Stage a. To a solution of 6-fluoropyridine-3-carboxylic acid (5.32 mmol) in DCM (20 ml) was added HATU (15.9 mmol). The reaction mixture was stirred at 0 ° C for 20 min. 3-Amino-1N-BOC-pyrrolidine (5.33 mmol) and DIPEA (15.96 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred at rt for 16 h. The resulting mixture was poured into a saturated NaHCO3 solution (80 ml) and extracted with EtOAc (2 x 40 ml). The organic layer was washed with 1M HCl (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (0-20% EtOAc in PE) yielding tert-butyl 3 - [(6-fluoropyridine-3-carbonyl) amino] pyrrolidine-1-carboxylate (3.88 mmol). MS: ES + 310.10; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.75 (d, J = 6.0 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.35 - 8.46 (m, 1H), 7.26-7.37 (m, 1H), 4.34-4.51 (m, 1H), 3.49-3.63 (m, 1H ), 3.33-3.43 (m, 2H), 3.16-3.27 (m, 1H), 2.05-2.18 (m, 1H), 1.84-1, 96 (m, 1H), 1.37-1.46 (m, 9H)
[0891] Stage b. To a solution of tert-butyl 3 - [(6-fluoropyridine-3-carbonyl) amino] pyrrolidine-1-carboxylate (0.2 mmol) and N-methyl-1-phenyl-methanamine (0.24 mmol) in DMF (1 ml) was added Cs2CO3 (0.6 mmol) at rt. The reaction was heated to 120 ° C for 16 h. The resulting mixture was concentrated under reduced pressure and the remainder was purified by prep TLC. (PE / EtOAc = 1: 2) yielding tert-butyl 3- (6- (benzyl (methyl) amino) -nicotinamido) pyrrolidine-1-carboxylate. MS: ES + 411.2
[0893] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 2 to provide the title compound (23.2 mg, 0.069 mmol). LCMS: Method F, RT 2.39 min, MS: ES + 336.2
[0895] Example 5 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-phenylazetidine-1-carboxamide
[0897] (Prepared according to general method E)
[0899]
[0902] Stage a. To a solution of (R) -3-amino-1 N-BOC-pyrrolidine (1.34 mmol) in water (5 ml) was added CDI (2.68 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. 3-Phenylazetidine (1.61 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 18 h. The resulting reaction mixture was poured into water (150 ml) and extracted with DCM (3 x 100 ml). The organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (1.5% MeOH in DCM) yielding tert-butyl (R) -3- (3-phenylazetidine-1-carboxamido) pyrrolidine-1-carboxylate (0.60 mmol). MS: ES + 346.1
[0903] Stage b. To a solution of tert-butyl (R) -3- (3-phenylazetidine-1-carboxamido) pyrrolidine-1-carboxylate (0.60 mmol) in DCM (5 ml) was added TFA (3.0 mmol) art. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was concentrated under reduced pressure and azeotroped with DCM (3x10 mL). The resulting residue was purified by triturating with diethyl ether (5 ml). The obtained material was dried under reduced pressure yielding the TFA salt of (R) -3-phenyl-N- (pyrrolidin-3-yl) azetidine-1-carboxamide (0.25 mmol). This substance was used directly for the next step without further purification. MS: ES + 246.53
[0905] Stage c. To a TFA salt solution of (R) -3-phenyl-N- (pyrrolidin-3-yl) azetidine-1-carboxamide (0.25 mmol) in DCM (5 ml) was added DIPEA (0.75 mmol) at 0 ° C and stirred for 10 min. Cyanogen bromide (0.37 mmol) was added to the reaction mixture at 0 ° C and stirred for an additional 30 min. The resulting reaction mixture was poured into ice water (100 ml) and extracted with DCM (3 x 50 ml). The organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (2.0% MeOH in DCM) yielding the title compound (0.08 mmol). LCMS: Method B, RT 3.26 min, MS: ES + 271.38; 1H NMR: (400MHz, DMSO-de) 5 ppm 7.32-7.38 (m, 4H), 7.23-7.27 (m, 1H), 6.58 (d, J = 6 , 4 Hz, 1H), 4.13-4.21 (m, 3H), 3.74-3.81 (m, 3H), 3.47-3.54 (m, 2H), 3.36-3.45 (m, 1H), 3.14-3.17 (m, 1H), 1.96-2.05 (m, 1H), 1.76-1.84 ( m, 1H).
[0906] Example 6 N- (( R) -1-cyanopyrrolidin-3-yl) -4- (( cis) -2,6-dimethylmorpholino) -3-fluorobenzamide
[0908] (Prepared according to general method F)
[0910]
[0913] Stage a. A mixture of methyl 4-bromo-3-fluorobenzoate (0.42 mmol), cis-2,6-dimethylmorpholine (0.42 mmol) and NaOtBu (0.42 mmol) in dry toluene (2 ml) was stirred at rt in a glass tube. The reaction mixture was purged with nitrogen for 10 min. Xantphos (0.021 mmol) and Pd2 (dba) 3 (0.009 mmol) were added to the reaction mixture and the glass tube was sealed. The resulting reaction mixture was heated at 110 ° C (external temperature) for 1 hr. Upon completion, the reaction mixture was cooled to rt and diluted with EtOAc (30 mL). The resulting reaction mixture was poured into water (40 ml). The mixture was extracted with EtOAc (2 x 20 ml). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (50% EtOAc in hexane) yielding methyl 4 - ((cis) -2,6-dimethylmorpholino) -3-fluorobenzoate (0.37 mmol). MS: ES + 268.3.
[0915] Stage b. To a solution of methyl 4- ((cis) -2,6-dimethylmorpholino) -3-fluorobenzoate (1.49 mmol) in THF: water (1: 1, 8 ml) was added LiOH (14.98 mmol ) art. The reaction mixture was stirred at 50 ° C for 4 h and then at rt for 15 h. The resulting reaction mixture was adjusted to pH 4 using a 1M HCl aqueous solution and the mixture was extracted with EtOAc (3 x 100 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding 4 - ((cis) -2,6-dimethylmorpholino) -3-fluorobenzoic acid (0.95 mmol). This substance was used directly for the next step without further purification. MS: ES + 254.26.
[0917] Stage c. To a solution of 4 - ((cis) -2,6-dimethylmorpholino) -3-fluorobenzoic acid (0.95 mmol) in DMF (3 ml) was added HATU (1.42 mmol) at rt. The reaction mixture was stirred at rt for 30 min. A solution of tert-butyl (R) -3-aminopyrrolidine-1-carboxylate (0.85 mmol) in DMF (1 mL) was added to the reaction mixture at rt. DIPEA (2.85 mmol) was added to the reaction mixture at rt. The resulting reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was poured into water (150 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was collected, washed with saturated NaHCO3 solution (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding (R) -3- (4- ( tert-Butyl (cis) -2,6-dimethylmorpholino) -3-fluorobenzamido) pyrrolidine-1-carboxylate (quantitative). This substance was used directly for the next step without further purification. MS: ES + 422.4.
[0919] Stages d, e. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 2 to provide the title compound (0.25 mmol). LCMS: Method A, RT 3.87 min, MS: ES + 346.98; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.48 (d, J = 6.4 Hz, 1H), 7.64 - 7.67 (m, 2H), 7.08 (t, J = 8.4 Hz, 1H), 4.43-4.47 (m, 1H), 3.71-3.75 (m, 2H), 3.60-3.64 (m, 1H ), 3.51-3.55 (m, 1H), 3.43-3.47 (m, 1H), 3.27-3.38 (m, 3H), 2.39-2, 45 (m, 2H), 2.11-2.15 (m, 1H), 1.90-1.95 (m, 1H), 1.13 (d, J = 6.4 Hz, 6 H)
[0921] Compounds in Table 1 were synthesized using general methods A-F as illustrated by Examples 1-6 using tert-butyl (rac) -3-aminopyrrolidine-1-carboxylate (CAS Number 186550-13-0).
[0923]
[0926] Table 1
[0928]
[0929]
[0930]
[0932] Compounds in Table 2 were synthesized using general methods AF as illustrated by Examples 1-6 using (R) -tert-butyl 3-aminopyrrolidine-1-carboxylate (CAS number 147081-49-0).
[0933] Table 2
[0934]
[0935]
[0937] The compounds in Table 3 were synthesized using general methods AF as illustrated by Examples 1-6 using tert-butyl (S) -3-aminopyrrolidine-1-carboxylate (CAS Number 147081-44-5).
[0938] Table 3
[0939]
[0941] Compounds in Table 4 were synthesized using general methods AF as illustrated by Examples 1-6 using tert-butyl (R) -3- (methylamino) pyrrolidine-1-carboxylate (Tarascon CAS Number 199336-83-9) .
[0942]
[0944] Table 4
[0945]
[0946]
[0948] The compounds in Table 5 were synthesized using general methods AF as illustrated by Examples 1-6 using tert-rac- (3aR, 6aR) -hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carboxylate. butyl (CAS number 180975-51-3).
[0949]
[0951] Table 5
[0952]
[0955] Example 62 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( N-methylisobutyramido) benzamide
[0957]
[0960] Stage a. To a solution of methyl 3-aminobenzoate (3.31 mmol) in DCM (10 ml) was added TEA (9.93 mmol) at rt and the reaction mixture was stirred at rt for 30 min. Isobutyryl chloride (4.96 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was then stirred at rt for 1 hr. The resulting reaction mixture was poured into water (100 ml) and extracted with DCM (2 x 50 ml). The combined organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure yielding methyl 3-isobutyramidobenzoate (quantitative). This substance was used directly for the next step without further purification. MS: ES + 222.2.
[0962] Stage b. To a solution of methyl 3-isobutyramidobenzoate (1.80 mmol) in THF (10 ml) was added NaH (60% mineral oil, 3.61 mmol) at 0 ° C. The reaction mixture was stirred at rt for 30 min. Methyl iodide (3.61 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was poured into ice water (50 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding methyl 3- (N-methylisobutyramido) benzoate (1.65 mmol). This substance was used directly for the next step without further purification. MS: ES + 236.6.
[0964] Stage c. To a solution of 3- (N-methylisobutyramido) benzoate (1.61 mmol) in THF: water (10: 2, 12 ml) was added UOH.H ² O (4.85 mmol) at 0 ° C. The reaction mixture was stirred at rt for 5 h. The resulting reaction mixture was adjusted to pH 3 by slowly adding an aqueous citric acid solution. The resulting mixture was extracted with EtOAc (3 x 20 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding 3- (N-methylisobutyramido) benzoic acid (1.44 mmol). This substance was used directly for the next step without further purification. MS: ES + 222.2
[0966] Stage d. To a solution of 3- (N-methylisobutyramido) benzoic acid (1.26 mmol) in THF (15 ml) was added HATU (1.90 mmol) and DIPEA (2.53 mmol) at 0 ° C. The reaction mixture was stirred at rt for 30 min. (R) -3-amino-1N-BOC-pyrrolidine (1.52 mmol) was added to the reaction mixture at rt and stirred for 2 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure, yielding tert-butyl (R) -3- (3- (N-methylisobutyramido) benzamido) pyrrolidine-1-carboxylate (quantitative) . This substance was used directly for the next step without further purification. MS: ES-388.6.
[0968] Stage e. To a solution of tert-butyl (R) -3- (3- (N-methylisobutyramido) benzamido) pyrrolidine-1-carboxylate (1.02 mmol) in DCM (15 ml) was added TFA (4 ml) to 0 ° C. The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was concentrated under reduced pressure yielding the TFA salt of (R) -3- (N-methylisobutyramido) -N- (pyrrolidin-3-yl) benzamide (0.99 mmol). This substance was used directly for the next step without further purification. MS: ES + 290.4.
[0969] Stage f. To a TFA salt solution of (R) -3- (N-methylisobutyramido) -N- (pyrrolidin-3-yl) benzamide (0.99 mmol) in THF (15 ml) was added K ² CO ³ ( 3.97 mmol) at rt. The reaction mixture was stirred at rt for 15 min. Cyanogen bromide (1.48 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 30 min. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (77% EtOAc in hexane) yielding the title compound (0.28 mmol). LCMS: Method B, RT 3.15 min, MS: ES + 315.1; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.64 (d, J = 6 Hz, 1H), 7.81 - 7.86 (m, 2H), 7.53 - 7.57 (m , 2H), 4.46-4.49 (m, 1H), 3.63-3.67 (m, 1H), 3.52-3.58 (m, 1H), 3.42 - 3.48 (m, 2H), 3.17 (s, 3H), 2.33-2.39 (m, 1H), 2.09-2.18 (m, 1H), 1 , 93-1.98 (m, 1H), 0.88-1.0 (m, 6H)
[0970] Example 63 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -5-phenylpyrimidine-2-carboxamide
[0972]
[0975] Stage a. To a solution of 5-bromopyrimidine-2-carboxylic acid (1.47 mmol) in 1,4-dioxane: water (3: 1.7 ml) were added phenylboronic acid (2.19 mmol) and Na2CO3 (2, 79 mmol) at rt in a glass tube. The reaction mixture was purged with nitrogen for 10 min. Pd (PPh3) 4 (0.14 mol) was added to the reaction mixture under nitrogen atmosphere and the glass tube was sealed. The reaction mixture was heated at 100 ° C (external temperature) for 2 h. The resulting reaction mixture was poured into a 1M NaOH solution (50 ml) and washed with diethyl ether (50 ml). The resulting aqueous layer containing the product was acidified with 1M HCl and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 5-phenylpyrimidine-2-carboxylic acid (1.25 mmol). MS: ES + 201.02, 1H NMR (400MHz, DMSO-d6) 5 ppm 13.62 (s, 1H), 9.30 (s, 2H), 7.89-7.91 (m, 2 H), 7.51-7.60 (m, 3H).
[0977] Stage b. To a solution of 5-phenylpyrimidine-2-carboxylic acid (0.60 mmol) in DCM (5 ml) were added HATU (0.90 mmol), TEA (1.20 mmol) and (R) -3-aminopyrrolidine Tert-Butyl -1-carboxylate. (0.60 mmol) at rt. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl (R) -3- (5-phenylpyrimidine-2-carboxamido) pyrrolidine-1-carboxylate (0.35 mmol ). This substance was used directly for the next step without further purification. MS: ES + 369.40.
[0979] Stage c. To a solution of tert-butyl (R) -3- (5-phenylpyrimidine-2-carboxamido) pyrrolidine-1-carboxylate (0.33 mmol) in DCM (5 ml) was added TFA (0.5 ml) at 0 ° C. The reaction mixture was stirred at rt for 6 h. The resulting reaction mixture was concentrated under reduced pressure. The resulting crude substance was triturated with diethyl ether (5 ml) yielding the TFA salt of (R) -5-phenyl-N- (pyrrolidin-3-yl) pyrimidine-2-carboxamide (0.30 mmol). This substance was used directly for the next step without further purification. MS: ES + 269.30.
[0981] Stage d. K2CO3 (0.54 mmol) at 0 ° C. Cyanogen bromide (0.40 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was poured into water (50 ml) and extracted with DCM (3 x 20 ml). The combined organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was triturated with diethyl ether (10 ml) yielding the title compound (0.15 mmol). LCMS: Method A, RT 3.34 min, MS: ES + 294.10; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.29 (s, 2H), 9.22 (d, J = 7.20 Hz, 1H), 7.89-7.91 (m, 2 H), 7.51-7.61 (m, 3H), 4.52-4.57 (m, 1H), 3.60-3.67 (m, 1H), 3.54-3 , 58 (m, 1H), 3.51-3.53 (m, 1H), 3.40-3.45 (m, 1H), 2.12-2.19 (m, 1H) , 1.99 - 2.08 (m, 1H)
[0982] Example 64 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( pyridin-4-yl) isoxazole-5-carboxamide
[0983] Stage a. To a solution of 4-pyridinecarboxaldehyde (28.04 mmol) in MeOH (30 ml) was added NH ² OH.HCl (55.94 mmol) at rt. The reaction mixture was heated to 60 ° C for 30 min. Precipitation was observed in the reaction mixture. The precipitates obtained were collected by filtration and dried under reduced pressure to yield isonicotinaldehyde oxime (23.77 mmol). This substance was used directly for the next step without further purification. MS: ES + 122.8; 1H NMR (400 MHz, DMSO-de) or ppm 12.78 (s, 1H), 8.89 (d, J = 6.40 Hz, 2H), 8.42 (s, 1H), 8 , 14 (d, J = 6.80 Hz, 2H)
[0985] Stage b. To a solution of isonicotinaldehyde oxime (22.95 mmol) in DMF (30 ml) was added NCS (34.36 mmol) at rt and stirred for 1 hr. The reaction mixture was cooled to 0 ° C and a solution of methyl propriolate (21.90 mmol) in DCM (5 ml) was added to the reaction mixture at 0 ° C all at once. TEA (43.56 mmol) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 3 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, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (26% EtOAc in hexane) yielding methyl 3- (pyridin-4-yl) isoxazole-5-carboxylate (2.45 mmol). MS: ES + 205.19.
[0987] Stage c. To a solution of methyl 3- (pyridin-4-yl) isoxazole-5-carboxylate (1.96 mmol) in THF (5 ml) was added TBD (3.79 mmol) at rt. Tert-butyl (R) -3-aminopyrrolidine-1-carboxylate (1.96 mmol) was added to the reaction mixture. The reaction mixture was stirred at rt for 3 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, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (2% MeOH in DCM) yielding tert-butyl (R) -3- (3- (pyridin-4-yl) isoxazole-5-carboxamido) pyrrolidine-1-carboxylate ( 0.33 mmol).). MS: ES + 358.90.
[0989] Stage d. To a solution of tert-butyl (R) -3- (3- (pyridin-4-yl) isoxazole-5-carboxamido) pyrrolidine-1-carboxylate (0.31 mmol) in DCM (2 ml) was added TFA (0.8 ml) at 0 ° C. The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was concentrated under reduced pressure. The resulting crude substance was triturated with diethyl ether (5 ml) yielding the TFA salt of (R) -3- (pyridin-4-yl) -N- (pyrrolidin-3-yl) isoxazole-5-carboxamide (0, 20 mmol). This substance was used directly for the next step without further purification. MS: ES + 259.20
[0991] Stage e. A solution of the TFA salt of (R) -3- (pyridin-4-yl) -N- (pyrrolidin-3-yl) isoxazole-5-carboxamide (0.18 mmol) in DCM (2 ml) was added K ² CO ³ (0.55 mmol) at 0 ° C. Cyanogen bromide (0.27 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was poured into water (50 ml) and extracted with DCM (3 x 20 ml). The combined organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (2% MeOH in DCM) to provide the title compound (0.07 mmol). LCMS: Method A, RT 2.90 min, MS: ES + 283.90; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.37 (d, J = 6.80 Hz, 1H), 8.77 (dd, J = 4.80, 1.60 Hz, 2H), 7.92 (dd, J = 4.40, 1.60 Hz, 2H), 7.82 (s, 1H), 4.48-4.52 (m, 1H), 3.63-3 , 67 (m, 1H), 3.53-3.59 (m, 1H), 3.44-3.49 (m, 1H), 3.34-3.38 (m, 1H) , 2.11-2.17 (m, 1H), 1.96-2.02 (m, 1H)
[0993] The compounds in Table 6 were synthesized using a procedure similar to that described for Example 64.
[0995]
[0998] Table 6
[1000]
[1001]
[1004] Example 273 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -N-methyl-3- ( 2-methylpyridin-4-yl) isoxazole-5-carboxamide
[1006]
[1009] Synthesized by a procedure similar to that described for Example 64 . LCMS: Method A, RT 3.22 min, MS: ES + 311.99; 1H NMR (400 MHz, MeOD) 5 ppm: 8.58 (d, J = 5.2 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 5.2 Hz , 1 HOUR),
[1010] 7.45-7.48 (m, 1H), 3.68-3.74 (m, 3H), 3.53-3.59 (m, 2H), 3.22 (s, 3H ), 3.65 (s, 3H), 2.26-2.33 (m, 2H).
[1011] Example 67 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -. 5-phenylpyridazine-3-carboxamide
[1013]
[1016] Stage a. A solution of 5-chloropyridazin-3 (2H) -one (9.96 mmol) and phenylboronic acid (11.95 mmol) was taken up in 1,4-dioxane (10 ml) in a glass tube. Na2CO3 (19.92 mmol) was added to the reaction mixture at rt as a 2M aqueous solution. The reaction mixture was purged with nitrogen for 10 min. Pd (dppf) Cl ² (4.98 mmol) was added to the reaction mixture at rt. The glass tube was hermetically sealed and heated at 110 ° C (external temperature) for 24 h. The resulting mixture was filtered through celite hyflow and washed with EtOAc (3 x 50 mL). Water (2 x 50 ml) was added to the filtrate. The organic layer phase was separated and washed with brine (100 ml), dried over NaSO ⁴ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (27% EtOAc in hexane) yielding 5-phenylpyridazin-3 (2H) -one (6.25 mmol). MS: ES + 172.79; 1H NMR (400 MHz, DMSO-de) 5 ppm 13.14 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.81 - 7.84 (m, 2 H), 7.53-7.54 (m, 3H), 7.14 (d, J = 2.4 Hz, 1H)
[1018] Stage b. POCl3 (22 ml) was added very slowly to a 100 ml round bottom flask containing 5-phenylpyridazin-3 (2H) -one (12.19 mmol) at rt. The reaction mixture was heated at 90 ° C for 1 hr. The resulting reaction mixture was carefully poured into ice-cold water (50 ml), made alkaline using solid NaHCO3 (pH adjusted 8 to 9), and extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with hexane (3 x 20 ml) and dried to yield 3-chloro-5-phenylpyridazine (12.06 mmol). This substance was used directly for the next step without further purification. MS: ES + 192.1.
[1020] Stage c. A solution of 3-chloro-5-phenylpyridazine (2.63 mmol) in MeOH: DMF (1: 1, 10 ml) was collected in a 25 ml glass tube at rt. TEA (3.95 mmol) was added to the reaction mixture at rt and stirred for 5 min. The reaction mixture was treated with dppf (0.26 mmol) and purged with nitrogen for 10 min. The resulting reaction mixture it was transferred to an autoclave under a nitrogen atmosphere. Pd (OAc) ² (0.13 mmol) was added to the reaction mixture at rt under nitrogen atmosphere. The reaction mixture was stirred in an autoclave at ^{0.69 bar (10 psi) CO 2} pressure at 70 ° C for 18 h. The resulting reaction mixture was carefully filtered through celite hyflow and washed with EtOAc (2 x 50 mL). Water (2 x 50 ml) was added to the filtrate. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (40% EtOAc in hexane) yielding methyl 5-phenylpyridazine-3-carboxylate (0.65 mmol). MS: ES + 215.18; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.86 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.99 - 8.04 (m, 2H), 7.57-7.64 (m, 3H), 4.00 (s, 3H)
[1022] Stage d. To a solution of methyl 5-phenylpyridazine-3-carboxylate (0.51 mmol) in THF (4 ml) was added TBD (0.77 mmol) at rt. A solution of (R) -3-amino-1N-BOC-pyrrolidine (0.51 mmol) in THF (1 ml) was added dropwise to the reaction mixture at rt. The reaction mixture was heated at 70 ° C for 12 h. The resulting reaction mixture was poured into water (50 ml), extracted with EtOAc (2 x 30 ml). The combined organic phase was washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (30% EtOAc in hexane) yielding tert-butyl 3- (5-phenylpyridazine-3-carboxamido) pyrrolidine-1-carboxylate (0.19 mmol). MS: ES + 369.19.
[1024] Stages e, f. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps d, e of Example 64 . LCMS: Method B, RT 3.25 min, MS: ES + 294.27; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.85 (d, J = 2.4 Hz, 1H), 9.62 (d, J = 7.2 Hz, 1H), 8.41 ( d, J = 2Hz, 1H), 8.00-8.07 (m, 2H),
[1025] 7.56-7.61 (m, 3H), 4.60-4.65 (m, 1H), 3.57-3.69 (m, 2H), 3.45-3.50 ( m, 2H), 2.07-2.21 (m, 2H))
[1026] Example 68 N- ( 1-cyanopyrrolidin-3-yl) -N-methyl- [1,1'-biphenyl] -4-carboxamide
[1028]
[1031] Stage a. To a solution of 4-phenylbenzoic acid (2.52 mmol) in THF (12.5 ml) was added T3P (50% in EtOAc) (7.56 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 min. Tert-Butyl 3-aminopyrrolidine-1-carboxylate (2.52 mmol) and DIPEA (7.56 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layer was washed with 1M HCl (30 ml), an aqueous NaHCO3 solution (30 ml), brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (25% EtOAc in hexane) yielding tert-butyl 3 - ([1,1'-biphenyl] -4-carboxamido) pyrrolidine-1-carboxylate (1.03 mmol) MS : ES + 367.28.
[1033] Stage b. To a solution of tert-butyl 3 - ([1,1'-biphenyl] -4-carboxamido) pyrrolidine-1-carboxylate (0.96 mmol) in DMF (9 ml) was added NaH (mineral oil 60 %, 1.95 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 min. Methyl iodide (1.45 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 10 min. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding 3- (N-methyl- [1, r-biphenyl] -4-carboxamido) pyrrolidine-1- tert-butyl carboxylate (1.18 mmol) MS: ES + 381.4
[1035] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1 . LCMS: Method A, RT 4.27 min, MS: ES + 305.94; 1H NMR (400MHz, DMSO-de) 5 ppm 7.63-7.68 (m, 2H), 7.61-7.62 (m, 2H), 7.47-7.51 (m, 4H), 7.40-7.43 (m, 1H), 5.13 (broad s, 1H), 3.63-3.68 (m, 2H), 3.45-3.48 (m, 2H), 3.03 (s, 3H), 2.13-2.21 (m, 2H)
[1036] Example 69 N- (( 3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -5-phenylthiazole-2-carboxamide Example 70 N- (( 3S, 4R) -1-cyano-4-methylpyrrolidin- 3-yl) -5-phenylthiazole-2-carboxamide
[1038]
[1040] Stage a. A solution of ethyl crotonate (17.5 mmol) and N-benzyl-O-ethyl-N - ((trimethylsilyl) methyl) hydroxylamine (19.2 mmol) in toluene (40 ml) was stirred at rt for 5 min. TFA (17.5 mmol) was added dropwise to the reaction mixture at rt. The reaction mixture was then heated at 50 ° C for 16 h. The resulting reaction mixture was poured into water (100 ml) and made alkaline with solid NaHCO3. The resulting mixture was extracted with EtOAc (2 x 180 ml). The combined organic phase was collected, dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (0-9% EtOAc in hexane) yielding ethyl (±) -trans-1-benzyl-4-methylpyrrolidine-3-carboxylate (9.0 mmol). MS: ES + 248.33; 1H NMR (400Mhz, CDCh) 5 ppm 7.24 - 7.36 (m, 5H), 4.13 (q, J = 8.0, 5.2 Hz 2H), 3.67 (d, J = 12.8 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 2.77-2.91 (m, 3H), 2.47-2.59 ( m, 2H), 2.21-2.26 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.16 (d, J = 6.71 Hz, 3H).
[1041] Stage b. To a solution of ethyl (±) -trans-1-benzyl-4-methylpyrrolidine-3-carboxylate (10 mmol) in EtOH (30 ml) was added polymethylhydrosiloxane (1.0 w / w), Pd (OH) ² at 20% on carbon (0.5 w / w) and BOC anhydride (20 mmol) at 0 ° C. The reaction mixture was stirred at rt for 1.5 h. The resulting reaction mixture was carefully filtered through celite hyflow and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (0-10% EtOAc in hexane) yielding 1-tertbutyl 3-ethyl (±) -4-methylpyrrolidine-1,3-dicarboxylate (8.5 mmol). MS: ES + 202.2 (M-tBu)
[1042] Stage c. A solution of 1-tert-butyl 3-ethyl (±) -4-methylpyrrolidine-1,3-dicarboxylate (8.5 mmol) in THF (15 ml) was stirred at 0 ° C for 5 min. A solution of NaOH (34.0 mmol) in water (15 ml) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was poured into water (200 ml) and acidified to pH 4.0 with dilute HCl. The obtained mixture was extracted with EtOAc (2 x 150 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding 1 - [(tert-butoxy) carbonyl] - (±) -trans-4-methylpyrrolidine-3-carboxylic acid (7.1 mmol). This substance was used directly for the next step without further purification. MS: ES-228.28; 1H NMR (400MHz, DMSO-d6) 5 ppm 12.51 (s broad, 1H), 3.47-3.56 (m, 2H), 3.28-3.34 (m, 1H) , 2.78-2.86 (m, 1H), 2.58-2.64 (m, 1H), 2.27-2.34 (m, 1H), 1.38 (s, 9 H), 1.04 (d, J = 4.8 Hz, 3H).
[1043] Stage d. To a solution of 1 - [(tert-butoxy) carbonyl] - (±) -trans-4-methylpyrrolidine-3-carboxylic acid (2.62 mmol) in toluene (7 ml) was added DIPEA (5.24 mmol ) and diphenylphosphorylazide (3.93 mmol) dropwise at 0 ° C. The reaction mixture was heated at 80 ° C for 3 h. The resulting reaction mixture was cooled to rt followed by the addition of 8M NaOH (2 ml). The reaction mixture was further heated at 80 ° C for 30 minutes. The resulting reaction mixture was poured into water (70 ml) and extracted with diethyl ether (2 x 70 ml) to remove non-polar impurities. The resulting aqueous layer was further extracted with DCM (3 x 70 ml). The combined DCM organic layer was dried over Na2SO4 and evaporated under reduced pressure to yield 1 - [(tert-butoxy) carbonyl] - (+) - trans-3-amino-4-methylpyrrolidine (1.17 mmol, quantitative) . This substance was used directly for the next step without further purification. MS: ES + 145.09 (M-tBu).
[1044] Stages e, f, g. The title compound was synthesized as a racemic mixture from the above intermediate using a procedure similar to that described for steps a, b, c of Example 1.
[1045] Stage h. The enantiomers were separated by preparative chiral HPLC; mobile phase: (A) 0.1% TFA in hexane (B) 0.1% TFA in EtOH, column: Chiralpak IB, 250 x 4.6 mm, 5 pm, flow rate: 1 ml / min.
[1046] Example 69 N- (( 3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -5-phenylthiazole-2-carboxamide
[1047] LCMS: Method B, RT 3.78 min, MS: ES + 313.22; Chiral HPLC: Method Y, RT 12.90 min; 1 H NMR (400 MHz, DMSO of) 5 ppm 8.82 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 7.99-8.016 (m, 2H), 7.52-7, 55 (m, 3H), 4.11-4.15 (m, 1H),
[1048] 3.73-3.77 (m, 1H), 3.66-3.70 (m, 1H), 3.25-3.29 (m, 1H), 3.09-3.13 (m, 1H), 2.26-2.33 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H).
[1050] Example 70 N- (( 3S, 4R) -1-cyano-4-methylpyrrolidin-3-yl) -. 5-phenylthiazole-2-carboxamide
[1052] LCMS: Method B, RT 3.78 min, MS: ES + 313.22; Chiral HPLC: Method Y, RT 15.61 min; 1H NMR (400MHz, DMSO-d6) 5 ppm 8.82 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 7.99-8.016 (m, 2H) , 7.52-7.55 (m, 3H), 4.11-4.15 (m, 1H),
[1053] 3.73-3.77 (m, 1H), 3.66-3.70 (m, 1H), 3.25-3.29 (m, 1H), 3.09-3.13 (m, 1H), 2.26-2.33 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H).
[1055] Example 71 N- (( 3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -2-phenylthiazole-5-carboxamide Example 72 N- (( 3S, 4R) -1-cyano-4-methylpyrrolidin- 3-yl) -2-phenylthiazole-5-carboxamide
[1057]
[1059] The title compounds were synthesized as a racemic mixture of the above intermediate using a similar procedure to that described for Examples 69/70 and the enantiomers were separated by preparative chiral HPLC; mobile phase: (A) 0.1% TFA in hexane (B) 0.1% TFA in IPA, column: Chiralpak IB, 250 x 4.6 mm, 5 pm, flow rate: 1 ml / min.
[1061] Example 71 N- (( 3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -2-phenylthiazole-5-carboxamide
[1063] LCMS: Method B, RT 4.21 min, MS: ES + 312.96; Chiral HPLC: Method Z, RT 14.29 min; 1 H NMR (400 MHz, DMSO-m 1 = 4 Hz 1 H 4 1 H 77 = 72 Hz 2 H 742 - 7 2 m H 41 - 42 m,
[1065]
[1067] Stage a. To a solution of 2-fluoropyridine-4-carboxylic acid (0.5 g, 3.50 mmol) in DCM (8 ml) were added HATU (2.01 g, 5.30 mmol) and DIPEA (0.91 g, 7.08 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C 20 min before adding tert-butyl (R) -3-aminopyrrolidine-1-carboxylate (CAS Number 147081-49-0) (0.52 g, 2.83 mmol) . The reaction mixture was stirred at rt for 4 h. The resulting reaction mixture was poured into water (100 ml) and extracted with DCM (3 x 50 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl (R) -3- (2-fluoroisonicotinamido) pyrrolidine-1-carboxylate (1.5 g, quantitative). MS: ES + 254.2 (M-56).
[1069] Stage b. K ² CO ³ (1, 33 g, 9.6 mmol) at rt and stirred for 10 min. A solution of isoindoline (CAS number 496-12-8) (0.63 g, 5.33 mmol) in DMF (1 ml) was added dropwise to the reaction mixture at rt. The reaction mixture was heated at 120 ° C for 18 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (3 x 40 ml). The combined organic phase was collected, washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (40% EtOAc in hexane) yielding tert-butyl (R) -3- (2- (isoindolin-2-yl) isonicotinamido) pyrrolidine-1-carboxylate (0.35 g, 0.85 mmol). MS: ES + 409.3
[1071] Stage c. A solution of tert-butyl (R) -3- (2- (isoindolin-2-yl) isonicotinamido) pyrrolidine-1-carboxylate (0.35 g, 0.85 mmol) in DCM (6 ml) was added added TFA (2 ml) at 0 ° C. The reaction mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The resulting residue was azeotropically distilled using DCM (2 x 20 ml). The resulting substance was triturated with n-pentane (2 x 20 ml), diethyl ether (2 x 20 ml) and finally dried yielding TFA salt of (R) -2- (isoindolin-2-yl) -N- ( pyrrolidin-3-yl) isonicotinamide (0.18 g, 0.42 mmol) MS: ES + 309.3
[1072] Stage d. A solution of the TFA salt of (R) -2- (isoindolin-2-yl) -N- (pyrrolidin-3-yl) isonicotinamide (0.18 g, 0.42 mmol) in THF (6 ml) was K ² CO ³ (0.23 g, 1.70 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 min before adding cyanogen bromide (0.045 g, 0.42 mmol). The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was poured into water (50 ml) and extracted with 5% MeOH in DCM (2 x 50 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting substance was triturated with n-pentane (2 x 30 ml), diethyl ether (2 x 30 ml) and further purified by preparative TLC using 3% MeOH in DCM as the mobile phase. The obtained material was further purified by preparative HPLC (mobile phase: 0.1% formic acid in water / MeCN; column: YMC ACTUS TRIART C ¹ 8 (250x20 mm), 5 pm; flow rate: 18 ml / min) yielding the title compound (0.033 g, 0.099 mmol). LCMS: Method A, RT 3.92 min, MS: ES + 334.01; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.76 (d, J = 6.8 Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H), 7.32 - 7.44 (m, 4H), 7.01 (d, J = 4.8Hz, 1H), 6.95 (s, 1H), 4.8 (s, 4H), 4.47 - 4.52 (m, 1H), 3.64-3.68 (m, 1H),
[1074] 3.54-3.60 (m, 1H), 3.34-3.49 (m, 1H), 3.30-3.31 (m, 1H), 2.13-2.18 ( m, 1H), 1.94-1.99 (m, 1H).
[1076] Example 74 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -2- ( 3,4-dihydroisoquinolin-2 ( 1H) -yl) isonicotinamide
[1078]
[1081] Synthesized using a procedure similar to that described for Example 73 using 1,2,3,4-tetrahydroisoquinoline (CAS number 91-21-4). LCMS: Method B, RT 3.34 min, MS: ES + 348.35
[1083] Example 75 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -2-fluoro-4- ( 4-methyl-1H-imidazol-1-yl) benzamide
[1085]
[1088] Stage a. A solution of acetic anhydride (0.89 g, 8.74 mmol) in formic acid (1.3 ml) was stirred at rt for 30 min. A solution of 4-amino-2-fluoro-benzoic acid methyl ester (CAS number 73792 08-2) (0.4 g, 2.36 mmol) in THF (4 ml) and the mixture of The reaction was then heated at 60 ° C for 16 h. The reaction mixture was poured into water (150 ml) and stirred at rt for 30 min. The precipitated solids were collected by vacuum filtration, washed with water (2 x 25 ml) and finally dried in vacuo yielding methyl 2-fluoro-4-formamidobenzoate (0.31 g, 1.56 mmol) MS: e S + 198.28
[1090] Stage b. To a solution of methyl 2-fluoro-4-formamidobenzoate (0.31 g, 1.56 mmol) in DMF (4 ml) was added K ² CO ³ (0.32 g, 2.34 mmol) and KI (0.025 g, 0.15 mmol) at rt. Chloroacetone (0.36g, 3.90mmol) was added dropwise to the reaction mixture and stirred at rt for 16h. The reaction mixture was poured into water (150 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was collected, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding methyl 2-fluoro-4- (N- (2-oxopropyl) formamido) benzoate ( 0.3 g, 1.18 mmol) MS: ES + 254.5.
[1092] Stage c. To a solution of 2-fluoro-4- (N- (2-oxopropyl) formamide) benzoate (0.3 g, 1.18 mmol) in glacial acetic acid (4 ml) was added ammonium acetate (0.54 g, 7.10 mmol) at rt. The reaction mixture was heated at 130 ° C for 3 h. The resulting reaction mixture was allowed to cool to rt and made alkaline using aqueous ammonium hydroxide to adjust to pH 7. The resulting aqueous solution was extracted with EtOAc (3 x 120 mL). The combined organic phase was collected, washed with water (100 ml), brine (150 ml), dried over Na2SO4, filtered and concentrated under reduced pressure yielding 2-fluoro-4- (4-methyl-1H-imidazole Methyl -1-yl) benzoate (0.32 g, 1.38 mmol) MS: ES + 235.2.
[1093] Stage d. To a solution of methyl 2-fluoro-4- (4-methyl-1 H-imidazol-1-yl) benzoate (0.32 g, 1.38 mmol) in THF: water (1: 1) was added UOH.H ² O (0.58 g, 13.80 mmol) at rt. The reaction mixture was stirred at rt for 8 h. The resulting reaction mixture was acidified using 1M HCl to adjust to pH 4. The resulting aqueous solution was extracted with EtOAc (3 x 150 ml). The desired product remained in the aqueous layer which was evaporated. The desired product is extracted from the obtained residue using 10% MeOH in DCM (40 ml). The obtained organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 2-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzoic acid (0.29 g, 1.31 mmol) MS: ES + 221.14.
[1095] Stage e. To a solution of 2-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzoic acid (0.29 g, 1.31 mmol) in DMF (5 ml) was added HATU (0, 8 g, 2.1 mmol) at rt. The reaction mixture was stirred at rt for 30 min. A solution of tert-butyl (R) -3-aminopyrrolidine-1-carboxylate (CAS number 186550-13-0) (0.19 g, 1.05 mmol) in DMF (1 mL) was added to the mixture of reaction at rt followed by the addition of DIPEA (0.51 g, 3.9 mmol) at rt. The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was poured into ice water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was collected and washed with saturated NaHCO3 solution (100 ml), brine (100 ml). The resulting organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding (R) -3- (2-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzamido) pyrrolidin-1 -tert-butyl carboxylate (0.3 g, 0.77 mmol) MS: ES + 389.4
[1097] Stage f. To a solution of tert-butyl (R) -3- (2-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzamido) -pyrrolidine-1-carboxylate (0.3 g, 0 , 77 mmol) in DCM (4 ml) was added TFA (0.586 ml, 7.73 mmol) at rt. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether (3 x 25 ml) and dried to yield TFA salt of (R) -2-fluoro-4- (4-methyl-1H-imidazol-1-yl) -N- ( pyrrolidin-3-yl) benzamide. (0.15 g, 0.37 mmol). This substance was used directly for the next step without further purification.
[1099] Stage g. To a TFA salt solution of (R) -2-fluoro-4- (4-methyl-1 H-imidazol-1-yl) -N- (pyrrolidin-3-yl) benzamide (0.15 g, 0 , 37 mmol) in THF (3 ml) were added K ² CO ³ (0.206 g, 1.49 mmol) and cyanogen bromide (0.039 g, 0.37 mmol) at rt. The reaction mixture was stirred at rt for 30 min. The reaction mixture was poured into water (70 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (100% EtOAc) yielding the title compound (0.020 g, 0.06 mmol) LCMS: Method A, RT 2.97 min, MS: ES + 313.98;
[1100] 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.68 (d, J = 6.8 Hz, 1H), 8.33 (s, 1H), 7.67 - 7.75 (m, 2 H), 7.57-7.60 (m, 2H), 4.44-4.47 (m, 1H), 3.61-3.65 (m, 1H), 3.43-3 , 55 (m, 2H), 3.28-3.31 (m, 1H), 2.16 (s, 3H), 2.08-2.13 (m, 1H), 1.88 - 1.96 (m, 1H).
[1102] Example 89 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -N-methyl-3-phenoxyazetidine-1-carboxamide
[1104] (Prepared according to general method E)
[1106]
[1109] Stage a. To a solution of tert-butyl (R) -3- (methylamino) pyrrolidine-1-carboxylate (CAS Number 199336-83-9) (0.22 g, 1.08 mmol) and TEA (0.5 ml, 3.59 mmol) in DCM (5 ml) was added triphosgene (0.1 g, 0.355 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. A solution of 3-phenoxy-azetidine hydrochloride (CAS number 301335-39-7) (0.2 g, 1.08 mmol) and TEA (0.25 ml, 1.80 mmol) were added to the reaction mixture at 0 ° C. The reaction mixture was allowed to warm to rt and stirred for 1 hour. The resulting reaction mixture was poured into a saturated NaHCO3 solution (50 ml) and extracted with DCM (3 x 25 ml). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5% MeOH in DCM) yielding tert-butyl (R) -3- (N-methyl-3-phenoxyazetidine-1-carboxamido) pyrrolidine-1-carboxylate (0.3 g , 0.80 mmol). ^l C ^m S: Method C, RT 2.25 min, MS: ES + 376.69.
[1111] Stages b, c. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 5 to provide the title compound. LCMS: Method A, RT 3.84 min, MS: ES + 301.21; 1H NMR (400 MHz, DMSO-de) 5 ppm 7.30 (t, J = 7.6 Hz, 2H), 6.97 (t, 7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 4.96-4.98 (m, 1H), 4.56-4.60 (m, 1H), 4.31-4.38 (m, 2H) , 3.83-3.89 (m, 2H), 3.37-3.52 (m, 3H), 3.24-3.28 (m, 1H), 2.68 (s, 3H), 1 , 89-1.98 (m, 2H).
[1113] Example 90 ( 3aR, 6aR) -5-cyano-N- ( 2-fluoro-4- ( trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 ( 2H) -
[1114] carboxamide
[1116]
[1119] Synthesized by a procedure similar to that described for Example 89 using (3aR, 6aR) -5-N-BOC-hexahydro-pyrrolo [3,4-b] pyrrole (CAS number 370882-39-6) in step a. LCMS: Method A, RT 4.19 min, MS: ES + 343.05; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.34 (s, 1H), 8.46 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 10.8 Hz, 1H), 7.52 (d, J = 7.6Hz, 1H), 4.37 (m, 1H), 3.51-3.61 (m, 4H), 3.41 - 3.45 (m, 1H), 3.24-3.28 (m, 1H), 2.96-2.98 (m, 1H), 2.02-207 (m, 1H) , 1.80-1.86 (m, 1H).
[1120] Example 91 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -2-fluoro-4- ( pyrimidin-2-ylamino) benzamide
[1121] (Prepared according to general method G)
[1123]
[1125] Stage a. To a solution of 4-amino-2-fluorobenzoic acid (0.4 g, 2.58 mmol) in THF (10 ml) was added HATU (1.46 g, 3.868 mmol) and DIPEA (1.3 ml, 7.74 mmol) at rt and stirred for 20 min. (R) -3-amino-1 N-BOC-pyrrolidine (0.52 g, 2.84 mmol) was added to the reaction mixture at rt and stirred for 4 h. The resulting reaction mixture was poured into water (30 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl (R) -3- (4-amino-2-fluorobenzamido) pyrrolidine-1-carboxylate (1.2 g , 3.71 mmol). LCMS: Method C, RT 1.99 min, MS: ES + 324.29.
[1126] Stage b. A mixture of tert-butyl (R) -3- (4-amino-2-fluorobenzamido) pyrrolidine-1-carboxylate (0.7 g, 2.16 mmol), 2-chloropyrimidine (0.24 g, 2.16 mmol), DBU (0.03 g, 1.73 mmol) and sodium tert-butoxide (0.31 g, 3.25 mmol) in toluene (15 ml) at rt. The reaction mixture was degassed for 10 min at rt and then racemic BINAP (0.013 g, 0.021 mmol) and Pd2 (dba) 3 (0.02 g, 0.021 mmol) were added to the reaction mixture. The reaction mixture was heated at 110 ° C for 12 h. The resulting reaction mixture was allowed to cool to rt and was poured into water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (1.5% MeOH in DCM) yielding tert-butyl (R) -3- (2-fluoro-4- (pyrimidin-2-ylamino) benzamido) pyrrolidine-1-carboxylate. (0.3 g, 0.75 mmol). LCMS: Method C, RT 2.04 min, MS: ES + 402.5.
[1127] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1 . LCMS: Method B, RT 2.98 min, MS: ES + 305.94; 1 H NMR (400 MHz, DMSO-de) or ppm 10.14 (s, 1 H), 8.58 (d, J = 5 Hz, 2 H), 8.35 (d, J = 5 Hz, 1 H ), 7.88-7.92 (m, 1H), 7.54-7.57 (m, 2H), 6.97 (t, J = 5Hz, 1H), 4.42-4.46 (m, 1H), 3.60-3.64 (m, 1H), 3.39-3.53 (m, 2H), 3.26-3.30 (m, 1H), 2.09 -2.13 (m, 1H), 1.89-1.94 (m, 1H)
[1128] Example 92 N- (( trans) -1-cyano-4-methylpyrrolidin-3-yl) -2-fluoro-4- (( R) -3-methoxypyrrolidin-1-yl) benzamide
[1129] (Prepared according to general method H)
[1131]
[1133] Step a was carried out using a procedure similar to that described for step a of Example 91 using 1 - [(tert-butoxy) carbonyl] - (±) -trans-3-amino-4-methylpyrrolidine (described in the synthesis of Examples 69/70 ).
[1134] Step b was carried out using a similar procedure to step a of Example 6
[1135] Steps cd were carried out using a procedure similar to steps cd of Example 91 . LCMS: Method B, RT 3.74 min, MS: ES + 347.32; 1H NMR (400 MHz, DMSO-de) 5 ppm 7.86 - 7.89 (m, 1H), 7.51 (t, J = 8.8 Hz, 1H), 6.30 - 6.41 (m, 2H), 4.11-4.15 (m, 2H), 3.61-3.68 (m, 2H), 3.43-3.45 (m, 1H), 3 , 27-3.33 (m, 2H), 3.25 (s, 3H), 3.21-3.24 (m, 2H), 3.05-3.10 (m, 1H) , 2.23-2.31 (m, 1H), 2.04-2.09 (m, 2H), 1.03 (d, J = 6.8Hz, 3H).
[1136] Example 93 2- ( 2-chlorophenyl) -N- (( trans) -1-cyano-4-hydroxypyrrolidin-3-yl) thiazole-5-carboxamide
[1138]
[1140] Synthesized by a procedure similar to that described for Example 2 , using ethyl 2-bromothiazole-5-carboxylate (CAS number 41731-83-3) in step ay (3R, 4R) -rel-3-amino-4-hydroxypyrrolidine Tert-Butyl -1-carboxylate (CAS number 148214-90-8) in step c. LCMS: Method A, RT 3.76 min, MS: ES + 348.84; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.86 (d, J = 6.8 Hz, 1H), 8.60 (s, 1H), 8.25- 8.27 (m, 1 H), 7.68-7.70 (m, 1H), 7.50-7.61 (m, 2H), 5.65 (dd, J = 16.4, 4.0 Hz, 1H ), 4.16-4.26 (m, 2H), 3.75-3.79 (m, 1H), 3.64-3.68 (m, 1H), 3.40-3, 43 (m, 1H), 3.24-3.27 (m, 1H).
[1141] Example 94 N- ( 1-cyano-3-methylpyrrolidin-3-yl) -2-fluoro-4- ( 1-methyl-1H-pyrazol-4-yl) benzamide
[1143]
[1145] Synthesized by a procedure similar to that described for Example 2 using tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (CAS number 1158758-59-8) in step c. LCMS: Method A, RT 3.43 min, MS: ES + 328.15; 1H NMR (400 MHz, CDCta) 5 ppm 8.04 (t, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 13.6 Hz, 1H), 6.73 (d, J = 16 Hz, 1H), 3.98 ( s, 3H), 3.89 (d, J = 10.4Hz, 1H), 3.58-3.66 (m, 2H), 3.52 (d, J = 10Hz, 1H ), 2.44-2.46 (m, 1H), 2.00-2.04 (m, 1H), 1.65 (s, 3H).
[1146]
[1147]
[1148]
[1149]
[1150]
[1151]
[1152]
[1153]
[1154] Example 150 N- (( R) -1-cyanopyrrolidin-3-yl) -5-methyl-1- ( 1-phenylethyl) -1H-pyrazole-3-carboxamide
[1156]
[1159] Stage a. To a stirred solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (1.0 g, 6.49 mmol) in THF (25 mL) was added KOH (0.435 g, 7.78 mmol) and stirred at rt for 15 min. The reaction was treated with (1-bromoethyl) benzene (1.2 g, 6.49 mmol) and heated at 80 ° C for 8 h. The resulting reaction mixture was allowed to cool to rt, quickly poured into water (40 ml) and extracted with EtOAc (3 x 30 ml). The combined organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography yielding the unwanted regio-isomer ethyl 3-methyl-1- (1-phenylethyl) -1H-pyrazole-5-carboxylate (0.12 g, 0.464 mmol) in EtOAc at 5% in hexane and ethyl regio-isomer 5-methyl-1- (1-phenylethyl) -1H-pyrazole-3-carboxylate (0.8 g, 3.10 mmol) in 12% EtOAc in hexane. LCMS: Method C, ^r T 2.20 min, ^m S: ES + 259.32; 1H NMR (400MHz, CDCl3) 5 ppm: 7.26 - 7.34 (m, 2H), 7.12 - 7.25 (m, 2H), 6.60 (s, 1H), 5 , 51 (q, J = 7.2 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.99 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8 Hz, 3H).
[1161] Stages b-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 2 to provide the title compound. LCMS: Method B, RT 3.71 min, MS: ES + 324.38; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.19 (d, J = 6.4 Hz, 1H), 7.31 - 7.35 (m, 2H), 7.26 - 7.27 (m, 1H), 7.16 (d, J = 7.2 Hz, 2H), 6.48 (s, 1H), 5.64-5.66 (m, 1H), 4, 46-4.48 (m, 1H), 3.58-3.62 (m, 2H), 3.51-3.53 (m, 1H), 3.41-3.46 (m, 1H), 2.16 (s, 3H), 2.08-2.11 (m, 1H), 1.95-2.05 (m, 1H), 1.83 (d, J = 6.8 Hz, 3H)
[1163] Example 151 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -5-methyl-1- ( pyridin-2-ylmethyl) -1H-pyrazole-3-carboxamide
[1165]
[1168] Synthesized by a procedure similar to that described for Example 150. LCMS: Method B, RT 2.82 min, MS: ES + 311.21; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.53 (dd, J = 4.8, 0.8 Hz, 1H), 8.32 (d, J = 7.2 Hz, 1H), 7.76 - 7.81 (m, 1H), 7.30 - 7.33 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.52 (s , 1H), 5.46 (s, 2H), 4.41-4.46 (m, 1H), 3.48-3.58 (m, 2H), 3.38-3.42 (m, 1H), 3.27-3.31 (m, 1H), 2.26 (s, 3H), 2.03-2.06 (m, 1H), 1.91-1 , 96 (m, 1H).
[1170] Example 152 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -2-fluoro-4- ( pyridazin-4-yl) benzamide
[1172]
[1175] Stage a. To a solution of 5-chloropyridazin-3 (2H) -one (0.50 g, 3.83 mmol) and 3-fluoro-4- (methoxycarbonyl) phenyl) boronic acid (0.91 g, 4.59 mmol) in 1,4-dioxane: water (9: 1, 10 mL) was added Na2CO3 (0.81 g, 7.66 mmol) at rt. The resulting reaction mixture was degassed for 20 min before adding Pd (dppf) Cl ² (0.14 g, 0.19 mmol) and the reaction mixture was heated at 100 ° C for 16 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was washed with brine (100 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was triturated with diethyl ether (2 x 10 ml) and vacuum filtered yielding methyl 2-fluoro-4- (6-oxo-1,6-dihydropyridazin-4-yl) benzoate (0.70 g, 2.82 mmol). This substance was used directly for the next step without further purification. LCMS: Method C, RT 1.66 min, MS: ES + 249.22; 1H NMR (400 MHz, DMSO-de) 5 ppm 13.24 (s, 1H), 8.35 (d, J = 1.60 Hz, 1H), 7.99 (t, J = 7.60 Hz, 1H), 7.91 (d, J = 12.40 Hz, 1H), 7.80 (d, J = 8.00 Hz, 1H), 7.31 (s, 1H), 3.88 (s, 3H).
[1176] Stage b. A solution of methyl 2-fluoro-4- (6-oxo-1,6-dihydropyridazin-4-yl) benzoate (0.90 g, 3.62 mmol) in POCta (1.06 ml, 1.08 mmol ) was heated at 100 ° C for 2 h. The resulting reaction mixture was cooled to rt and poured into ice water (20 ml). The pH was adjusted to ~ 7-8 using solid NaHCO3. The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding methyl 4- (6-chloropyridazin-4-yl) -2-fluorobenzoate (1.1 g, quantitative). This substance was used directly for the next step without further purification. LCMS: Method C, RT 1.96 min, MS: ES + 267.26.
[1177] Stage c. A solution of methyl 4- (6-chloropyridazin-4-yl) -2-fluorobenzoate (1.10 g, 4.10 mmol) in EtOAc: MeOH (1: 1, 20 mL) was prepared in an autoclave. Ammonium formate (0.51 g, 8.21 mmol) and ^{20% Pd (OH) 2} on carbon (0.5 g, 0.71 mmol) were added to the reaction mixture at rt. The reaction mixture was heated at 80 ° C for 16 h. The resulting reaction mixture was cooled to rt and carefully filtered through celite hyflow. The celite pad was washed carefully with MeOH (5 x 30 ml). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (2% MeOH in DCM) yielding methyl 2-fluoro-4- (pyridazin-4-yl) benzoate (0.17 g, 0.73 mmol). LCMS: Method C, RT 1.69 min, MS: ES + 233.26; 1H NMR (400MHz, DMSO-d6) or ppm 9.73-9.74 (m, 1H), 9.36-9.37 (m, 1H), 8.03-8.15 (m, 3H), 7.93-7.94 (m, 1H), 3.90 (s, 3H)
[1178] Stages dg. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps be of Example 2. LC ^m S: Method A, RT 2.68 min, MS: ES + 312.32; 1 H NMR (400 MHz, DMSO-d6) or ppm 9.72 - 9.73 (m, 1H), 9.34 (dd, J = 5.60, 1.20 Hz, 1H), 8.82 (d, J = 6.40 Hz, 1H), 8.11 (dd, J = 5.60, 2.80 Hz, 1H), 7.99 (dd, J = 11.60, 1.60 Hz, 1H), 7.89 (dd, J = 8.40, 2.00 Hz, 1H), 7.74 (t, J = 7.60 Hz, 1H), 4.44 -4, 51 (m, 1H), 3.63-3.70 (m, 1H), 3.39-3.56 (m, 2H), 3.28-3.32 (m, 1H), 2.09-2.18 (m, 1H), 1.89-1.97 (m, 1H)
[1179] Example 153 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -1-isobutyl-6- ( 1-methyl-1H-pyrazol-4-yl) -1H-indazole-3-carboxamide
[1181]
[1184] Stage a. To a mixture of 6-bromoindoline-2,3-dione (5 g, 22.12 mmol) in water (55 ml) was added NaOH (0.97 g, 24.3 mmol) at rt. The reaction mixture was stirred at rt for 30 min. A solution of NaNO ² (1.68 g, 24.3 mmol) in 30 ml of water was added dropwise to the reaction mixture at 5 ° C over a period of 30 min. The reaction mixture was stirred at 5 ° C for 20 min. The resulting reaction mixture was transferred to a dropping funnel and added dropwise to a solution of H ² SO ⁴ (4.5 ml) in water (55 ml) at a temperature below 10 ° C over a period of 25 min. The resulting reaction mixture was stirred at 10 ° C for 20 min. A solution of tin (II) chloride (10.06 g, 53.1 mmol) in concentrated HCl (21 ml) was added dropwise to the reaction mixture at 5 ° C. The reaction mixture was stirred at 5 ° C for 2 h. The resulting reaction mixture was vacuum filtered. The desired solids were washed with hexane (4 x 50 mL) and dried under high vacuum to yield 6-bromo-1H-indazole-3-carboxylic acid (5.95 g, 24.9 mmol). LCMS: Method C, RT 1.66 min, MS: ES + 239.20, 241.20
[1186] Stage b. To a solution of 6-bromo-1H-indazole-3-carboxylic acid (5.95 g, 24.9 mmol) in MeOH (95 ml) was added H ² SO ⁴ (5.8 ml, 58.0 mmol ) art. The reaction mixture was heated at 90 ° C for 3.5 h. The resulting reaction mixture was concentrated under reduced pressure. The residue obtained was poured into a saturated aqueous NaHCO3 solution (250 ml) and extracted with EtOAc (4 x 200 ml). The combined organic layer was washed with brine (2 x 150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (11% EtOAc in hexane) yielding methyl 6-bromo-1H-indazole-3-carboxylate (1.81 g, 7.98 mmol). LCMS: Method C, RT 2.08 min, MS: ES + 255.13, 257.10.
[1188] Stage c. To a mixture of 6-bromo-1H-indazole-3-carboxylic acid (0.25 g, 0.98 mmol) in DMF (3 ml) and water (3 ml) was added 1-methyl-4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (0.30 g, 2.07 mmol) at rt, followed by NaHCO3 (0.33 g, 3 , 92 mmol). The reaction mixture was degassed with N ² for 15 min, PdCl ² (dppf) (0.071 g, 0.098 mmol) was added to the reaction mixture at rt. The reaction mixture was heated to 140 ° C for 1.5 h. The resulting reaction mixture was poured into cold water (150 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3- methyl carboxylate (0.31 g, 1.21 mmol). LCMS: Method A, RT 3.29 min, MS: ES + 256.19.
[1190] Stage d. To a solution of methyl 6- (1-methyl-1H-pyrazol-4-yl) -1H-indazole-3-carboxylate (0.31 g, 1.21 mmol) in DMF (7 ml) was added CS ² CO ³ (0.59 g, 1.81 mmol) and 1 -iodo-2-methylpropane (0.16 ml, 1.45 mmol) at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into cold water (150 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding a mixture of 1-isobutyl-6- (1-methyl-1H-pyrazol-4-yl) Methyl -1 H-indazole-3-carboxylate (0.027 g, 0.08 mmol) LCMS: Method C, RT 2.24 min, MS: ES + 313.38, 1 H NMR (400 MHz, DMSO-de) or ppm 8.29 (s, 1H), 8.03 (d, J = 4.8 Hz, 2H), 8.0 (s, 1H), 7.57 (dd, J = 1.2, 8 , 4Hz, 1H), 4.33 (d, J = 7.2Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.27-2 , 33 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H) and 2-isobutyl-6- (1-methyl-1H-pyrazol-4-yl) -2H-indazole Methyl -3-carboxylate (0.007 g, 0.022 mmol). LCMS: Method C, Rt 2.40 min, MS: ES + 313.43.
[1192] Stages huh. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps be of Example 2. LCMS: Method A, RT 3.98 min, MS: ES + 392.23; 1 H NMR (400 MHz, DMSO-de) 5 ppm 8.60 (d, J = 7.2 Hz, 1H), 8.28 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.50 (d, J = 8.4Hz, 1H), 4.54-4.58 (m, 1H) , 4.30 (d, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.55-3.66 (m, 2H), 3.39-3.47 ( m, 2H), 2.33-2.37 (m, 1H), 2.11-2.16 (m, 1H), 2.01-2.06 (m, 1H), 0, 90 (d, J = 6.4 Hz, 6H).
[1193] Example 154 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -6- ( 3,5-dimethylisoxazol-4-yl) -1-isobutyl-1H-indazole-3-carboxamide
[1195] Procedure similar to that described for Example 153 using 3,5-dimethylisoxazole acid 4-114-47-9) in step c. LCMS: Method A, RT 4.54 min, MS: ES + 407.07; 1H NMR (400 7 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.27 ( dd, J = 8.8, J = 1.2 Hz, .35 (d, J = 7.2 Hz, 1H), 3.55 - 3.66 (m, 2H), 3.33 - 3 , 48 (m, 2H), 2.44-2.46 (m, 4H), 2.15 (m, 2H), 0.85-0.89 (m, 6H).
[1196] nopyrrolidin-3-yl) -1- ( cyclopropylmethyl) -6- ( 3,5-dimethylisoxazol-4-yl) -1H-indazol-3-
[1198] Procedure similar to that described for Example 154 using cyclopropylmethyl bromide in step d. LCMS: Method A, RT 4.37 min, MS: ES + 404.99; 1H NMR (400MHz, DMSO-z, 1H), 8.22 (d, J = 8.4Hz, 1H), 7.83 (s, 1H), 7.28 (dd, J = 8 , 4.1.2 Hz, 1H), 4.56-4.61H), 3.56-3.67 (m, 2H), 3.39-3.48 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 2.13-2.18 (m, 14-1.38 (m, 1H), 0.44-0.54 (m, 4H).
[1199] opyrrolidin-3-yl) -N-methyl-6- ( 1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide
[1201] Procedure similar to that described for Example 3 using (R) -3- (methylamino) pyrrolidin-1-CAS number 199336-83-9). LCMS: Method A, RT 2.87 min, MS: ES + 350.17; ^r M ⁿ H1 (400 2 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.58 (dd, J = H), 3.54-3.64 (m, 2H), 3.43-3.47 (m, 3H), 3.37 (s, 3H), 2.07-2.17 (m; 2H). Opyrrolidin-3-yl) -N-methyl-5- ( 1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide
[1203] Similar procedure to that described for Example 3 using (R) -3- (methylamino) pyrrolidin-1-CAS number 199336-83-9). LCMS: Method A, RT 3.38 min, MS: ES + 349.11; ^r M ⁿ H1 (400 56 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.41 (s, 2H), 6.85 (s, 1H), 5.16 (t, J = 3.57-3.66 (m, 2H), 3.40-3.49 (m, 2H), 3.13 (s, 3H), 2.08-2.17 (m, 2H).
[1204]
[1206] Synthesized by a procedure similar to that described for Example 3 using tert-butyl (R) -3- (methylamino) pyrrolidine-1-carboxylate (CAS number 199336-83-9). LCMS: Method B, RT 3.45 min, MS: ^e S + 365.3; ^r M ⁿ H1 (400 MHz, DMSO-d6) 5 ppm 13.02 (s, 1H), 7.49 - 7.82 (m, 2H), 7.28 (s, 1H), 3, 59-3.71 (m, 2H), 3.44-3.54 (m, 3H), 3.02-3.09 (m, 3H), 2.42 (s, 3H), 2.24 (s, 3H), 2.13-2.21 (m, 2H).
[1208] Example 159 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -7- ( 1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-3-carboxamide
[1210]
[1213] Stage a. To a solution of 7-bromo-imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (0.2 g, 0.743 mmol) in THF: water (1: 1) (12 ml) was added UOH.H ² O (0.062 g, 1.49 mmol) at 0 ° C. The reaction mixture was stirred at rt for 6 h. The resulting reaction mixture was acidified to pH 4 by dropwise addition of a 10% citric acid solution and stirred for 10 min. The resulting solids were vacuum filtered and dried to yield 7-bromoimidazo [1,2-a] pyridine-3-carboxylic acid (0.16 g, 0.666 mmol). LCMS: Method C, RT 1.39 min, MS: ES + 241.08, 242.99
[1215] Stages b-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 3 to provide the title compound. LCMS: Method B, RT 2.76 min, MS: ES + 336.32; 1H NMR (400 MHz, DMSO-de) or ppm 9.33 - 9.37 (m, 1H), 8.54 (d, J = 6.4 Hz, 1H), 8.38 (s, 1 H), 8.35 (s, 1H), 8.10 (s, 1H), 7.90 (d, J = 0.8Hz, 1H), 7.40 (dd, J = 2Hz , 7.2 Hz, 1H), 4.51-4.55 (m, 1H), 3.89 (s, 3H), 3.65-3.69 (m, 1H), 3, 54-3.60 (m, 1H), 3.44-3.50 (m, 1H), 3.31-3.35 (m, 1H), 2.12-2.21 (m, 1H), 1.94-2.01 (m, 1H)
[1216] Example 160 ( R) -7- ( 3-cyanophenyl) -N- ( 1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-3-carboxamide
[1218] yield similar to that described for Example 159. LCMS: Method A, RT 3.69 min, MS: Hz, DMSO-de) 5 ppm 9.48 (d, J = 7.6 Hz, 1H), 8.68 (d, J = 6.8 Hz, 1H), 8.44 (s, 1H), 0 - 8.25 (m, 2H), 7.91 (d, J = 8 Hz, 1H), 7 , 73 (t, J = 7.6Hz, 1H), 7.62 (dd, J = 2Hz, 7.6Hz, 7-3.71 (m, 1H), 3.55-3.61 ( m, 1H), 3.47-3.51 (m, 1H), 3.33-3.36 (m, 1H), 2.15-2.20
[1220] opyrrolidin-3-yl) -N-methyl-7- ( 2-methylpyridin-4-yl) imidazo [1,2-a] pyridine-3-carboxamide
[1222] yield similar to that described for Example 159. LCMS: Method A, RT 3.04 min, MS: Hz, DMSO-de) 5 ppm 9.04 (d, J = 7.2 Hz, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), .73 (d, J = 5.2 Hz, 1H), 7.59 (dd, J = 2, 0 Hz, 7.6 Hz, 1H), 5.11-5.15 (m, 1H), 3.57-3.69), 3.13 (s, 3H), 2.57 (s , 3H), 2.10-2.22 (m, 2H)
[1224] opyrrolidin-3-yl) -N-methyl-7- ( 6-methylpyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxamide
[1226] yield similar to that described for Example 159. LCMS: Method A, RT 3.15 min, MS: Hz, DMSO-d6) 5 ppm 9.03 (d, J = 7.2 Hz, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.14-8.20 (m, 2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 5, 12-5.15 (m, 1H), 3.57-3.69 (m, 2H), 3.40-3.50 (s, 3H), 2.10-2.21 (m, 2H)
[1228]
[1230] Synthesized by a procedure similar to that described for Example 159. LCMS: Method A, RT 3.06 min, MS: ES + 364.15; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.94 (d, J = 7.2 Hz, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7 , 67 (s, 1H), 7.27 (dd, J = 7.2, 2Hz, 1H), 5.08-5.15 (m, 1H), 3.81 (s, 3H ), 3.56-3.67 (m, 2H), 3.39-3.47 (m, 2H), 3.11 (s, 3H), 2.41 (s, 3H), 2.08-2.23 (m, 2H).
[1231] Example 164 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -7- ( 2,6-dimethylpyridin-4-yl) -N-methylimidazo [1,2-a] pyridine-3-carboxamide
[1233]
[1236] Stage a. To a solution of 5-bromopyridin-2-amine (5 g, 28.9 mmol) in toluene (30 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (CAS Number 13089-11-7 ) (4.5 g, 28.9 mmol) and pyridine (4.65 ml, 57.8 mmol) at rt. The reaction mixture was stirred at rt for 5 min before SOCl ² (3.43 g, 28.9 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was poured into cold water (200 ml) and made alkaline with solid NaHCO3. The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (1% EtOAc in hexane) yielding methyl (Z) -2 - ((5-bromopyridin-2-yl) imino) -3,3,3-trifluoropropanoate (5 g, 16.07 mmol). LCMS: Method C, RT 2.75 min, m S: ES + 313.10, 315.10
[1238] Stage b. To a solution of methyl (Z) -2 - ((5-bromopyridin-2-yl) imino) -3,3,3-trifluoropropanoate (5 g, 16.1 mmol) in MeCN (50 mL) was added trimethyl phosphite (2.99 g, 24.1 mmol) at rt. The reaction mixture was heated at 80 ° C for 24 h. The resulting reaction mixture was cooled to rt and poured into cold water (150 ml) followed by the addition of a ^{5% K 2} CO ³ solution (100 ml). The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (25% EtOAc in hexane) yielding methyl 6-bromo-3-fluoroimidazo [1,2-a] pyridine-2-carboxylate (1.5 g, 5.49 mmol) . LCMS: Method C, RT 1.94 min, MS: ES + 273.10, 275.13
[1240] Stage c. A mixture of methyl 6-bromo-3-fluoroimidazo [1,2-a] pyridine-2-carboxylate (1.5 g, 5.49 mmol) in concentrated HCl was heated at 100 ° C for 2.5 h. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was azeotroped with DCM (3 x 10 ml) and dried under reduced pressure to yield the HCl salt of 6-bromo-3-fluoroimidazo [1,2-a] pyridine-2-carboxylic acid (1, 2 g, 4.06 mmol). LCMS: Method C, RT 1.68 min, MS: ES 259.30, 261.30
[1241] Stages d-g. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 3 to provide the title compound. LCMS: Method A, RT 3.80 min, MS: ES + 374.99; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.83 (s, 1H), 8.76 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8 , 16 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.80 (dd, J = 1.6 Hz, 9.6 Hz , 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 4.50 -4.55 (m, 1 H), 3.54-3.63 (m, 2H), 3.37-3.47 (m, 2H), 2.01-2.14 (m, 2H).
[1242] The compounds in Table 8 were synthesized using a procedure similar to that described for Example 167.
[1244]
[1246] Table 8
[1248]
[1251] Example 172 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -2-fluoro-4- ( pyrazolo [1,5-a] pyrimidin-5-yl) benzamide
[1253]
[1255] Stage a. A solution of 3-fluoro-4- (methoxycarbonyl) phenyl) boronic acid (CAS number 505083-04-5) (0.50 g, 2.50 mmol) in THF: water (5: 2, 14 ml) was UOH.H ² O (0.32 g, 7.57 mmol) was added at 0 ° C. The reaction mixture was stirred at rt for 24 h, then heated at 60 ° C for 1 h. The resulting reaction mixture was cooled to rt and acidified using a 1M HCl solution. The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 4-borono-2-fluorobenzoic acid (0.42 g, 2.31 mmol). LCMS: Method C, RT 1.32 min, MS: ES-183.20; 1H NMR (400 MHz, DMSO-d6) 5 ppm 13.22 (s, 1H), 8.42 (s, 2H), 7.81 (t, J = 7.60 Hz, 1H), 7 , 65 (d, J = 7.60 Hz, 1H), 7.59 (d, J = 4.00 Hz, 1H) Steps be. The title compound was synthesized from the above intermediate using a procedure similar to that of described for Example 3 to provide the title compound. LCMS: Method A, RT 3.38 min, MS: ES + 351.04; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.27 (d, J = 7.60 Hz, 1H), 8.82 (d, J = 6.80 Hz, 1H), 8.29 ( d, J = 2.40 Hz, 1H), 8.13-8.18 (m, 2H), 7.75-7.77 (m, 2H), 6.83 (d, J = 2 , 40 Hz, 1H), 4.47 - 4.49 (m, 1H), 3.63 - 3.67 (m, 1H), 3.40-3.56 (m, 2H), 3 , 28-3.30 (m, 1H), 2.10-2.17 (m, 1H), 1.91-1.96 (m, 1H)
[1256] Example 173 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -5- ( 4-fluorophenyl) picolinamide
[1258]
[1260] Stage a. To a solution of methyl 5-bromopicolinate (CAS number 29682-15-3) (1 g, 4.62 mmol) in THF (10 ml) was added DIPEA (1.79 g, 13.9 mmol) and ( Tert-Butyl R) -3-aminopyrrolidine-1-carboxylate (1.03 g, 5.55 mmol) at rt followed by trimethylaluminum (2 M in toluene) (11.5 ml, 2.34 mmol). The reaction mixture was heated to 70 ° C for 2 h. The resulting reaction mixture was poured into a saturated NH4Cl solution (150 ml) and the mixture was filtered through celite hyflow. The celite pad was washed with EtOAc (50 ml). The filtrate was 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 purified by column chromatography (20% EtOAc in hexane) yielding tert-butyl (R) -3- (5-bromopicolinamido) pyrrolidine-1-carboxylate (1.2 g, 3.24 mmol). LCMS: Method C, RT 2.34 min, MS: ES + 314.18, 316.18 [M-56]; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.94 (d, J = 7.2 Hz, 1H), 8.77-8.78 (m, 1H), 8.26 (dd, J = 2.8Hz, 1H), 7.96 (d, J = 8.4Hz, 1H), 4.42-4.45 (m, 1H), 3.48-3.58 (m , 1H), 3.37-3.39 (m, 1H), 3.21-3.29 (m, 2H), 1.97-2.06 (m, 2H), 1.40 (s, 9 H)
[1261] Stages b-d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-d of Example 3 to provide the title compound. LCMS: Method A, RT 4.15 min, MS: ES + 311.06; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.06 (d, J = 7.2 Hz, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.28 ( dd, J = 2.4 Hz, 8.4 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.85 - 7.89 (m, 2H), 7 , 39 (t, J = 8.8 Hz, 2H), 4.53-4.57 (m, 1H), 3.54-3.64 (m, 2H), 3.39-3, 48 (m, 2H), 2.02-2.16 (m, 2H)
[1262] Example 174 N - ((cis) -1 -cyano-2-methylpyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide
[1264]
[1266] Synthesized as a racemic mixture using a similar procedure to that described for Example 2 using cis-3-amino-1-BOC-2-methylpyrrolidine (CAS number 1374653-02-7) in step c. LCMS: Method A, RT 4.35 min, MS: ES + 324.96; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.96 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.85 - 7.89 (m, 2H), 7.39 (t, J = 8.8 Hz, 2H), 4.54-4.59 (m, 1H), 3.82-3.87 (m, 1H), 3.63-3.68 (m, 1H), 3.37 - 3.43 (m, 1H), 2.07-2.21 (m, 2H), 1.08 (t, J = 6.4Hz, 3H).
[1267] Example 175 3-chloro-N- (( trans) -1-cyano-4-methylpyrrolidin-3-yl) -4-morpholinobenzamide
[1269]
[1271] Synthesized as a racemic mixture using a procedure similar to that described for Examples 69/70 using 3-chloro-4-morpholinobenzoic acid (CAS number 26586-20-9) in step e. LCMS: Method B, RT 3.66 min, MS: ES + 349.10; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.52 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 2.0, 1H), 7.81 (dd , J = 8.0, 1.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.09-4.14 (m, 1H), 3.75 (t, J = 4.8, 4H), 3.63-3.72 (m, 2H), 3.21-3.25 (m, 1H), 3.06-3.11 (m , 1H), 3.04 (t, J = 4.4, 4H), 2.24-2.33 (m, 1H), 1.99 (d, J = 6.8, 3H) .
[1272] Example 176 N - ((trans) -1 -cyano-4-fluoropyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide
[1274]
[1276] Stage a. To a solution of 4-phenylbenzoic acid (0.110 g, 0.555 mmol) in THF (5 ml) was added DIPEA (0.110 g, 0.852 mmol) and HATU (0.243 g, 0.639 mmol) at rt and stirred for 30 min. Tert-butyl trans-3-amino-4-fluoropyrrolidine-1-carboxylate (CAS number 1363382-79-9) (0.100 g, 0.427 mmol) was added to the mixture of reaction. The resulting reaction mixture was stirred at rt for 1.5 h. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with EtOAc (2 x 25 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography (10% EtOAc in hexane) yielding trans-tert-butyl 3 - ([1,1'-biphenyl] -4-carboxamido) -4-fluoropyrrolidine-1-carboxylate (0.170 g , 0.443 mmol). LCMS: Method C, RT 2.52 min, MS: ES-383.45; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.72 (d, J = 6.4 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.73 - 7.82 (m, 4H), 7.48-7.52 (m, 2H), 7.40-7.43 (m, 1H), 4.52-4.54 (m, 1H ), 3.63-3.69 (m, 2H), 3.52-3.58 (m, 1H), 3.44-3.50 (m, 2H), 1.44 (s, 9H).
[1278] Stage b. A solution of tert-butyl trans-3 - ([1,1'-biphenyl] -4-carboxamido) -4-fluoropyrrolidine-1-carboxylate (0.150 g, 0.390 mmol) in formic acid (7.5 mL) was prepared at rt. ). The resulting reaction mixture was stirred at 50 ° C for 3 h. The resulting reaction mixture was evaporated under reduced pressure. The material obtained was co-evaporated with DCM (2 x 30 ml) and dried in vacuo yielding the formic salt of trans-N- (4-fluoropyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide (0.140 g, quantitative). LCMS: Method C, RT 1.83 min, MS: ES + 285.22.
[1280] Stage c. The title compound was synthesized from the above intermediate using a similar procedure to that described for step c of Example 1. LCMS: Method H, RT 26.23 min, MS: ES + 309.92; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.75 (d, J = 6.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.97 ( d, J = 8.1 Hz, 2H), 7.73-7.75 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.40-7, 44 (m, 1H), 5.12-5.24 (m, 1H), 4.54-4.61 (m, 1H), 3.82-3.89 (m, 1H), 3.65-3.76 (m, 2H), 3.56-3.59 (m, 1H).
[1282] Example 177 N- (( cis) -1-cyano-4-cyclopropylpyrrolidin-3-yl) -3-fluoro-4- ( 1-methyl-1H-pyrazol-4-yl) benzamide
[1283] Stage a. A solution of tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (CAS Number 114214-49-2) (1.00 g, 5.405 mmol) in THF (40 mL) cooled to -30 ° C and treated with a complex of methyl sulfide and copper (I) bromide (0.221 g, 1.078 mmol). A 0.5M solution of cyclopropylmagnesium bromide in THF (41 mL, 20.5 mmol) was added dropwise to the reaction mixture at -30 ° C. The reaction mixture was allowed to warm to -10 ° C and stirred for 1 hr. The resulting mixture was poured into a saturated NH4Cl solution (500 ml) and extracted with EtOAc (2 x 70 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (30% EtOAc in hexane) yielding trans-tert-butyl 3-cyclopropyl-4-hydroxypyrrolidine-1-carboxylate (1.70 g, 7.49 mmol). LCMS: Method A, RT 3.91 min, MS: ES + 228.00; 1H NMR (400 MHz, DMSO-ds) 5 ppm: 4.97 (d, J = 4.0 Hz, 1H), 3.97-3.99 (m, 1H), 3.59-3, 72 (m, 1H),
[1284] 3.35-3.47 (m, 2H), 3.02-3.07 (m, 2H), 1.37 (s, 9H), 0.55-0.60 (m, 1H ), 0.33-0.45 (m, 2H), 0.17-0.23 (m, 1H), 0.06-0.12 (m, 1H).
[1286] Stage b. To a solution of tert-butyl trans-3-cyclopropyl-4-hydroxypyrrolidine-1-carboxylate (1.70 g, 7.49 mmol) in THF (20 ml) was added NaH (60% dispersion in oil of paraffin, 0.898 g, 37.42 mmol) at rt. The reaction mixture was stirred at 50 ° C for 1 hr. The resulting reaction mixture was cooled to rt. A solution of p-toluenesulfonyl chloride (2,800 g, 14.74 mmol) in THF (10 mL) was added dropwise to the reaction mixture and stirred for 16 h. The resulting reaction mixture was poured into water (500 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (17% EtOAc in hexane) yielding tert-butyl trans-3-cyclopropyl-4- (tosyloxy) pyrrolidine-1-carboxylate (1,500 g, 3.94 mmol). LCMS: Method C, RT 2.65 min, MS: ES + 326.30 (M-56).
[1288] Stage c. NaN3 (4,700 g, 72 , 31 mmol) at rt. The reaction mixture was heated at 60 ° C for 16 h. The resulting reaction mixture was cooled to rt and poured into cold water (400 ml). The resulting mixture was extracted with EtOAc (2 x 70 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl cis-3-azido-4-cyclopropylpyrrolidine-1-carboxylate (1.00 g, quantitative). This substance was used directly for the next step without further purification.
[1290] Stage d. To a solution of tert-butyl cis-3-azido-4-cyclopropylpyrrolidine-1-carboxylate (1.00 g, 3.97 mmol) in MeOH (20 ml) was added 10% Pd on carbon (dry) (1.00 g) at rt. The reaction mixture was purged with hydrogen for 2 h. The resulting reaction mixture was carefully filtered through celite hyflow and the obtained filtrate was concentrated under reduced pressure yielding tert-butyl cis-3-amino-4-cyclopropylpyrrolidine-1-carboxylate (0.570 g, 2.52 mmol) . LCMS: Method A, RT 3.75 min, MS: ES + 227.00. This substance was used directly for the next step without further purification.
[1292] Stages eg. The title compound was synthesized from the above intermediate using a similar procedure to that described for Example 1. LCMS: Method B, RT 3.64 min, MS: ES + 354.60; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.56 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.72-7.78 (m, 2H), 4.64-4.68 (m, 1H), 3 , 91 (s, 3H), 3.68-3.72 (m, 1H), 3.52-3.57 (m, 1H), 3.37-3.47 (m, 2H) , 1.68-1.74 (m, 1H), 0.69-0.85 (m, 1H), 0.39-0.42 (m, 2H), 0.35-0.38 (m, 2H).
[1293] Example 178 N- (( trans) -1-cyano-4-methoxypyrrolidin-3-yl) -N-methyl-4- ( 1-methyl-1H-pyrazol-4-yl) benzamide
[1295]
[1298] Stage a. To a solution of ethyl 4-bromobenzoate (4.00 g, 17.47 mmol) in 1,4-dioxane (10 ml) was added 1-methyl-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1 H-pyrazole (CAS number 761446-44-0) (5.44 g, 26.20 mmol) at rt. The resulting reaction mixture was degassed for 30 min before the addition of Pd (PPh3) 4 (0.201 g, 0.174 mmol) and K ² CO ³ (4.82 g, 34.93 mmol) at rt. The reaction mixture was heated at 90 ° C for 15 h. The resulting reaction mixture was cooled to rt and poured into saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (2 x 100 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding ethyl 4- (1-methyl-1H-pyrazol-4-yl) benzoate (4.00 g, 17.39 mmol). LCMS: Method C, rT 2.124 min, MS: ES + 231.10. This substance was used directly for the next step without further purification.
[1300] Stage b. To a solution of ethyl 4- (1-methyl-1H-pyrazol-4-yl) benzoate (4.00 g, 17.39 mmol) in THF (25 ml) was added a solution of NaOH (1.40 g, 35.0 mmol) in water (10 ml) at rt. The reaction mixture was heated at 80 ° C for 15 h. The resulting reaction mixture was cooled to rt and poured into water (20 ml). The resulting mixture was extracted with EtOAc (100 ml). The resulting aqueous layer was acidified with a dilute HCl solution. The obtained solids were filtered and washed with water (20 ml). The obtained solid substance was dried under high vacuum yielding 4- (1-methyl-1H-pyrazol-4-yl) benzoic acid (2,500 g, 12,376 mmol). LCMS: Method C, RT 1.586, MS: ES + 203.01. This substance was used directly for the next step without further purification.
[1302] Stage c. To a solution of tert-butyl trans-3-hydroxy-4- (methylamino) pyrrolidine-1-carboxylate (CAS Number 203503-49-5) (0.800 g, 3.703 mmol) in THF (10 mL) was added acid 4- (1-methyl-1H-pyrazol-4-yl) benzoic (0.90 g, 4.44 mmol), HATU (2.80 g, 7.37 mmol) and DIPEA (2 ml, 11.11 mmol) ) art. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was poured into water (20 ml) and extracted with EtOAc (4 x 25 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10% MeOH in DCM) yielding trans-3-hydroxy-4- (N-methyl-4- (1-methyl-1H-pyrazol-4-yl) benzamido) pyrrolidin- Tert-Butyl 1-carboxylate (0.170 g, 0.425 mmol). LCMS: Method C, RT 1.90 min, MS: ES + 401.65.
[1304] Stage d. To a solution of tert-butyl trans-3-hydroxy-4- (N-methyl-4- (1-methyl-1H-pyrazol-4-yl) benzamido) pyrrolidine-1-carboxylate (0.250 g, 0.625 mmol) NaH (60% dispersion in paraffin oil, 0.061 g, 1.54 mmol) was added in DMF (3 ml) at 0 ° C. Methyl iodide (0.264 g, 1.86 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was poured into ice water (10 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10% MeOH in DCM) yielding trans-3-methoxy-4- (N-methyl-4- (1-methyl-1H-pyrazol-4-yl) benzamido) pyrrolidin-1 -tert-butyl carboxylate (0.250 g, 0.603 mmol). LCMS: Method C, RT 2.08 min, MS: ES + 415.75.
[1306] Stages e, f. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1. LCMS: Method A, RT 3.17 min, MS: ES + 340.06; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.22 (s, 1H), 7.93 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7 , 39 (d, J = 7.6 Hz, 2H), 4.09-4.13 (m, 1H), 3.87 (s, 3H), 3.67-3.76 (m, 3H), 3.54-3.58 (m, 1H), 3.42-3.45 (m, 1H), 3.28 (s, 3H), 2.91 (s, 3H ).
[1308] Example 179 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -5- ( 1,3-dimethyl-1H-pyrazol-4-yl) picolinamide
[1310]
[1313] Synthesized by a procedure similar to that described for Example 173. LCMS: Method A, RT 3.01 min, MS: ES + 311.06; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.96 (d, J = 6.8 Hz, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 8 , 02 (s, 2H), 4.51-4.54 (m, 1H), 3.82 (s, 3H), 3.53-3.64 (m, 2H), 3.38 - 3.48 (m, 2H), 2.35 (s, 3H), 2.03-2.13 (m, 2H) Example 180 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -5- ( 2-methyl-6- ( trifluoromethyl) pyrimidin-4-yl) picolinamide
[1315]
[1318] Stage a. To a solution of tert-butyl (R) -3- (5-bromopicolinamido) pyrrolidine-1-carboxylate (0.5 g, 1.35 mmol) (prepared according to the method described for Example 173 step a) in THF ( 15 ml) bis (pinacholate) diboron (0.51 g, 2.02 mmol) was added at rt. CH ³ COOK (0.26 g, 2.70 mmol) and X-Phos (0.064 g, 0.13 mmol) were added to the reaction mixture at rt. The reaction mixture was degassed with N ² for 15 min before adding Pd2 (dba) 3 (0.062 g, 0.067 mmol). The reaction mixture was heated at 90 ° C for 6 h. The resulting mixture was poured into water (200 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine (200 ml) and dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (10% MeOH in DCM) yielding (R) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) tert-butyl picolinamido) pyrrolidine-1-carboxylate (0.2 g, 0.19 mmol). LCMS: Method A, RT 2.10 min, MS: ES + 336.07.
[1320] Stages b-d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-d of Example 3 to provide the title compound. LCMS: Method B, RT 4.03 min, MS: ES + 377.12; 1H NMR (400 MHz, DMSO-de) or ppm 9.49 (s, 1H), 9.18 (d, J = 7.2 Hz, 1H), 8.86 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 8.59 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 4.55-4.59 (m, 1H ), 3.55-3.66 (m, 2H), 3.41-3.49 (m, 2H), 2.84 (s, 3H), 2.04-2.18 (m, 2H)
[1322] Example 181 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -4- ( 2,6-dimethylpyrimidin-4-yl) -2-fluorobenzamide
[1324]
[1327] Stage a. To a solution of 4-bromo-2-fluorobenzoic acid (35.0 g, 159.81 mmol) in THF (800 ml) was added DIPEA (82.4 ml, 479 mmol) at 0 ° C. HATU (91.1 g, 240 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at 0 ° C for 45 min. Tert-butyl (R) -3-aminopyrrolidine-1-carboxylate (29.7 g, 160 mmol) was added dropwise to the reaction mixture at 0 ° C. The resulting reaction mixture was stirred for 15 min at 0 ° C and then at rt for 2 h. The resulting mixture was poured into water (1500 ml) and extracted with EtOAc (3 x 500 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (35% EtOAc in hexane) yielding tert-butyl (R) -3- (4-bromo-2-fluorobenzamido) pyrrolidine-1-carboxylate (50.50 g, 130 mmol ). LCMS: Method C, RT 2.37 min, MS: ES + 387.23; 1H NMR (400 MHz, DMSO-de) or ppm 8.65 (d, J = 6.80 Hz, 1H), 7.65 - 7.67 (m, 1H), 7.48 - 7.54 (m, 2H),
[1328] 4.36-4.39 (m, 1H), 3.47-3.56 (m, 1H), 3.30-3.40 (m, 2H), 3.14-3.18 ( m, 1H), 2.05-2.08 (m, 1H), 1.83-1.86 (m, 1H), 1.45 (s, 9H).
[1330] Stage b. To a solution of tert-butyl (R) -3- (4-bromo-2-fluorobenzamido) pyrrolidine-1-carboxylate (2.75 g, 8.33 mmol) in DMF (10 mL) was added bis ( pinacolato) diboro (2.53 g, 9.99 mmol) at rt followed by CH ³ COOK (2.55 g, 26.0 mmol). The resulting reaction mixture was degassed for 10 min. Pd (dppf) Cl ² -CH ² Cl ² (0.34 g, 0.41 mmol) was added and the reaction mixture heated at 100 ° C for 6.5 h. The reaction mixture was cooled to rt. The resulting reaction mixture was poured into ice water (125 ml) and extracted with DCM (4 x 25 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was diluted with water (1200 ml) and extracted with DCM (4 x 100 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding (R) -3- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Tert-butyl 2-yl) benzamido) pyrrolidine-1-carboxylate (2.20 g, 5.07 mmol). This substance was used directly for the next step without further purification. LCMS: Method C, RT 1.93 min, MS: ES + 353.30
[1332] Stage c. To a solution of (R) -3- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamido) pyrrolidine-1-carboxylate of tert- Butyl (0.250 g, 0.576 mmol) in 1,4-dioxane: water (8: 2, 10 mL) was added K ² CO ³ (0.238 g, 1.724 mmol) followed by 4-chloro-2,6-dimethylpyrimidine ( CAS number 4472-45-1) (0.082 g, 0.576 mmol) at rt. The reaction mixture was degassed for 30 min. PdCb (dppf) (0.042 g, 0.057 mmol) was added to the reaction mixture at rt. The reaction mixture was heated at 100 ° C for 3 h. The resulting reaction mixture was cooled to rt and concentrated under pressure. reduced. The resulting reaction mixture was poured into water (25 ml) and extracted with EtOAc (2 x 25 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography (70% EtOAc in hexane) yielding (R) -3- (4- (2,6-dimethylpyrimidin-4-yl) -2-fluorobenzamido) pyrrolidine-1-carboxylate of tertiary butyl (0.110 g, 0.265 mmol). LCm S: Method C, 2.18, MS: ES + 415.38
[1333] Stages d, e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps c, d of Example 3. LCMS: Method B, RT 3.64 min, MS: ES + 340.10; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.79 (d, J = 6.80 Hz, 1H), 8.06 - 8.12 (m, 2H), 7.91 (s, 1 H), 7.71-7.75 (m, 1H), 4.46-4.50 (m, 1H), 3.63-3.67 (m, 1H), 3.44-3 , 56 (m, 2H), 3.27-3.32 (m, 1H), 2.66 (s, 3H), 2.51 (s, 3H), 2.12-2.17 (m, 1H), 1.91-1.96 (m, 1H).
[1335] The compounds in Table 9 were synthesized using a procedure similar to that described for Example 181.
[1337]
[1340] 183 N ^ N fluoro-4- ( 2- 1 H), 4.47 - 4.50 (m, 1 H), 3.66 - 3.67 (m, 1 H), B 3.94 ^{ES +}
[1341] trifluoromethyl irimidin- 342 - 351 m 3 H 214 - 217 m 1 H 191 - _380.11
[1343]
[1346] Example 186 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-fluoro-5- ( pyrazolo [1,5-a] pyrim idin-5-yl) picolinamide
[1348]
[1351] Synthesized by a procedure similar to that described for Example 181, using 5-bromo-3-fluoroopicolinic acid (CAS number 669066-91-5) in step a and 5-chloropyrazolo [1,5-a] pyrimidine (CAS number 29274- 24 6) in step c. LCMS: Method A, RT 3.19 min, MS: ES + 352.10; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.36 (d, J = 7.6 Hz, 1H), 9.30 (s, 1H), 9.13 (d, J = 6.8 Hz, 1H), 8.63 (dd, J = 1.6 Hz, 11.6 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.85 (d , J = 7.6 Hz, 1H), 6.89-6.90 (m, 1H), 4.51-4.53 (m, 1H), 3.63-3.67 (m, 1H), 3.53-3.57 (m, 1H), 3.38-3.46 (m, 1H), 3.36-3.38 (m, 1H), 2.13 - 2.18 (m, 1H), 1.99-2.02 (m, 1H)
[1352] Example 187 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-fluoro-5- ( imidazo [1,2-a] pyridin-6-yl) picolinamide
[1354]
[1357] Synthesized by a procedure similar to that described for Example 186. LCMS: Method A, RT 3.02 min, MS: ES + 351.04; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.19 (s, 1H), 9.02 (d, J = 6.4 Hz, 1H), 8.88 (s, 1H), 8 , 29 (d, J = 12.8 Hz, 1H), 8.00 (s, 1H), 7.73 (s, 2H), 7.67 (s, 1H), 4.05 - 4.54 (m, 1H), 3.63-3.67 (m, 1H), 3.46-3.58 (m, 2H), 3.36-3.38 (m, 1H ), 2.12-2.33 (m, 1H), 1.97-2.04 (m, 1H)
[1359] Example 188 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-methoxy-3-phenylazetidine-1-carboxamide
[1361]
[1364] Stage a. To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (CAS Number 398489-26-4) (10 g, 58.41 mmol) in THF (100 ml) was added phenyl magnesium bromide (1 M in THF) (64.2 ml, 64.25 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h and then at rt for 16 h. The reaction mixture was poured into a saturated NH4Cl solution (150 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layer was washed with water (2 x 50 ml), brine (2 x 50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in hexane) yielding tert-butyl 3-hydroxy-3-phenylazetidine-1-carboxylate (11.92 g, 47.8 mmol). LCMS: Method C, RT 2.22 min, MS: ES + 194.1 [M-56], 1H NMR (400 MHz, DMSO-de) 5 ppm 7.49 (d, J = 7.2 Hz, 2H ), 7.38 (t, J = 8 Hz, 2H), 7.27-7.31 (m, 1H), 6.33 (s, 1H), 4.03 (s, 4H) , 1.41 (s, 9H)
[1366] Stage b. To a solution of tert-butyl 3-hydroxy-3-phenylazetidine-1-carboxylate (1 g, 4.01 mmol) in MeCN (40 mL) was added NaH (60% dispersion in paraffin oil, 0, 3 g, 7.63 mmol) at rt. The reaction mixture was stirred at rt for 30 min. A solution of methyl iodide (0.75 g, 5.28 mmol) in MeCN (5 mL) was added dropwise to the reaction mixture at rt and stirred for 4 h. The resulting mixture was poured into water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic phase was washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding tert-butyl 3-methoxy-3-phenylazetidine-1-carboxylate (1.13 g, 4.29 mmol). LCMS: Method C, RT 2.39 min, MS: ES + 208.01 [M-56], 1H NMR (400 MHz, DMSO-de) 5 ppm 7.34-7.50 (m, 5H), 4 .03-4.11 (m, 4H), 2.96 (s, 1H), 1.39 (s, 9H)
[1368] Stage c. To a solution of tert-butyl 3-methoxy-3-phenylazetidine-1-carboxylate (1.12 g, 4.24 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1.4 -dioxane (10 ml) dropwise at rt. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was evaporated under reduced pressure and the obtained residue was triturated with n-pentane (20 ml), diethyl ether (20 ml) and dried in vacuo to yield the HCl salt of 3-methoxy-3-phenylazetidine. (0.7 g, 3.5 mmol). LCMS: Method C, RT 1.50 min, MS: ES + 164.04
[1370] Stages df. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 89. LCMS: Method B, ^r T 3.38 min, MS: ES + 301.20; 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.34 - 7.46 (m, 5H), 6.65 (d, J = 6.4 Hz, 1H), 4.14 (t, J = 5.6 Hz, 1H), 4.02-4.07 (m, 4H), 3.44-3.52 (m, 2H),
[1371] 3.45-3.40 (m, 1H), 3.13-3.16 (m, 1H), 2.98 (s, 3H), 1.95-2.07 (m, 1H ), 1.75-1.83 (m, 1H).
[1373] Example 189 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -N-methyl-3-phenylazetidine-1-carboxamide
[1375]
[1378] Stage a. A solution of phenylboronic acid (0.65 g, 5.33 mmol) in IPA (4.5 ml) was prepared in a microwave safe glass tube. Nil2 (0.05 g, 0.15 mmol) and rans-2-aminocyclohexanol hydrochloride (0.024 g, 0.15 mmol) were added to the reaction mixture at rt. Sodium bis (trimethylsilyl) amide (1M in THF) (5.3 mL, 5.28 mmol) was added dropwise to the reaction mixture at rt. N-BOC-3-iodoazetidine (CAS number 254454-54-1) (0.75 g, 2.65 mmol) was added, the glass tube was sealed and the reaction mixture was subjected to microwave heating at 80 ° C for 50 min. The reaction mixture was cooled to rt and evaporated under reduced pressure to produce a colored residue black. The resulting residue was purified by column chromatography (6% EtOAc in hexane) yielding tert-butyl 3-phenylazetidine-1-carboxylate (1.3 g, 5.57 mmol). LCMS: Method C, RT 2.47 min, MS: eS + 234.4 Step b. To a solution of tert-butyl 3-phenylazetidine-1-carboxylate (1.2 g, 5.15 mmol) in DCM was added TFA (3.6 ml) at 0 ° C. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was evaporated under reduced pressure. The residue was azeotroped with diethyl ether (10 mL) and dried in vacuo to yield the TFA salt of 3-phenylazetidine (0.3 g, 1.21 mmol). This substance was used directly for the next step without further purification. LCMS: Method C, RT 1.08 min, MS: ES + 134.19
[1379] Stages ce. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 89 to provide the title compound. LCMS: Method A, RT 3.88 min, MS: ES + 285.18; 1H NMR (400MHz, DMSO-d6) 5 ppm 7.34-7.38 (m, 4H), 7.24-7.27 (m, 1H), 4.59-4.63 (m, 1H), 4.26 - 4.32 (m, 2H), 3.85 - 3.91 (m, 2H), 3.75 - 3.79 (m, 1H), 3.44 - 3.53 (m, 2H), 3.25-3.40 (m, 2H), 3.71 (s, 3H), 1.91-2.01 (m, 2H). Example 190 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( 4-methoxyphenyl) azetidine-1-carboxamide
[1381] Similar procedure to that described for steps a, b of Example 189, using 4-ido acid from steps a-c of Example 5. LCMS: Method A, RT 3.44 min, MS: ES + 301.08; NMR ppm 7.25 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 6.4 Hz, 1 H), 4.12-4.20 3-3.73 (m, 3H), 3.45-3.53 (m, 2H), 3.37-3.41 (m, 1H), 3.13-3.17 (m, 1H), 1.96-2.04H).
[1382]
[1384] Synthesized using a procedure similar to that described for steps a, b of Example 189, using 4-chlorophenylboronic acid, followed by steps a-c of Example 5. LCMS: Method A, RT 3.86 min, MS: ES + 304.94; 1H NMR (400 MHz, DMSO-de) 5 ppm 7.36-7.43 (m, 4H), 6.59 (d, J = 6.4 Hz, 1H), 4.12 - 4.22 (m, 3H), 3.73-3.79 (m, 3H), 3.45-3.77 (m, 2H), 3.34-3.41 (m, 1H), 3 , 13-3.17 (m, 1H), 1.98-2.03 (m, 1H), 1.78-1.82 (m, 1H).
[1385] Example 192 ( R) -3- ( 3-chlorophenyl) -N- ( 1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide
[1387]
[1389] Synthesized using a procedure similar to that described for steps a, b of Example 189, using 3-chlorophenylboronic acid, followed by steps a-c of Example 5. LCMS: Method B, RT 3.75 min, MS: ES + 305.22; 1H NMR (400 MHz, DMSO-de) 5 ppm 7.38 - 7.41 (m, 2H), 7.32 (d, J = 7.2 Hz, 2H), 6.58 (d, J = 6.8 Hz, 1H), 4.13-4.20 (m, 3H), 3.77-3.78 (m, 3H), 3.45-3.53 (m, 2H ), 3.35-3.39 (m, 1H), 3.13-3.17 (m, 1H), 1.96-2.09 (m, 1H), 1.77-1, 83 (m, 1H).
[1390] Example 193 ( 3aR, 6aR) -1- ( 3-phenylazetidine-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 ( 1H) -carbonitrile
[1392]
[1394] Synthesized by a procedure similar to that described for Example 189. LCMS: Method A, RT 3.82 min, MS: ES + 297.09; 1H NMR (400MHz, DMSO-de) 5 ppm 7.35-7.39 (m, 4H), 7.24-7.28 (m, 1H), 4.35-4.40 (m, 1H) 4.20-4.27 (m, 2H), 3.92-3.96 (m, 1H), 3.76-3.86 (m, 3H), 3.50-3 , 55 (m, 2H), 3.37-3.42 (m, 2H), 3.16-3.23 (m, 1H), 2.87-2.89 (m, 1H) , 1.74-1.78 (m, 1H), 1.74-1.78 (m, 1H).
[1395] Example 194 ( R) -1- ( 1-cyanopyrrolidin-3-yl) -1-methyl-3- ( 4- ( 1-methyl-1H-pyrazol-4-yl) phenyl) urea
[1397]
[1399] Stage a. To a mixture of 4-bromoaniline (3 g, 17.4 mmol) in DMF: water (8: 2) (60 ml) was added 1-methyl-4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -1H-pyrazole (CAS number 761446-44-0) (3.62 g, 17.4 mmol) and Na2CO3 (3.69 g, 34.8 mmol) at rt . The reaction mixture was degassed with N2 for 10 minutes before adding PdCb (dppf) (1.27 g, 1.74 mmol). The resulting reaction mixture was heated at 110 ° C for 2.5 h. The resulting reaction mixture was poured into cold water (300 ml) and extracted with EtOAc (3 x 300 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 4- (1-methyl-1H-pyrazol-4-yl) aniline (1.8 g, 10.39 mmol). LCMS: Method A, RT 2.84 min, MS: ES + 173.97, 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.85 (s, 1H), 7.63 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H), 3.81 (s, 3H).
[1400] Stage b. To a solution of 4- (1-methyl-1H-pyrazol-4-yl) aniline (0.5 g, 2.89 mmol) in DCM (10 ml) was added pyridine (0.69 ml, 8, 67 mmol) and 4-nitrophenyl chloroformate (0.057 g, 4.33 mmol) at rt. The reaction mixture was stirred at rt for 2 h. (R) -3- (methylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (0.693 g, 3.46 mmol) was added to the reaction mixture at rt and stirred for a further 16 h. The resulting reaction mixture was poured into cold water (100 ml) and extracted with DCM (3 x 100 ml). The combined organic layer was washed with 1% citric acid (1 x 100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to yield (R) -3- (1-methyl Tert-Butyl -3- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) ureido) pyrrolidin-1-carboxylate (0.6 g, 1.50 mmol). LCMS: Method C, RT 2.07 min, MS: ES + 400.40.
[1401] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 5 to provide the title compound. LCMS: Method A, RT 3.14 min, MS: ES + 325.03; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.35 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.41-7.46 ( m, 4H), 4.88-4.92 (m, 1H), 3.84 (s, 3H), 3.50-3.56 (m, 2H), 3.35-3, 39 (m, 1H), 3.27-3.31 (m, 1H), 2.88 (s, 3H), 1.94-2.03 (m, 2H).
[1402] Example 195 ( R) -1- ( 1-cyanopyrrolidin-3-yl) -1-methyl-3- ( 4- ( trifluoromethyl) phenyl) urea
[1404]
[1406] Stage a. To a solution of 4-chloro-2-fluoroaniline (CAS number 57946-56-2) (0.500 g, 3.434 mmol) in chloroform (10 ml) was added DIPEA (0.891 g, 6.906 mmol) at 0 ° C. 4-Nitrophenyl chloroformate (0.831 g, 4.122 mmol) was added portionwise to the reaction mixture at 0 ° C. The reaction mixture was heated to 60 ° C for 2.5 h. The resulting reaction mixture was cooled to rt and poured into water (70 ml). The resulting mixture was extracted with DCM (3 x 40 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (11% EtOAc in hexane) yielding 4-nitrophenyl (4-chloro-2-fluorophenyl) carbamate (0.230 g, 0.740 mmol).
[1407] Stage b. To a solution of 4-nitrophenyl (4-chloro-2-fluorophenyl) carbamate (0.220 g, 0.709 mmol) in pyridine (10 ml) was added (3aR, 6aR) -hexahydropyrrolo [3,4-b] pyrrole- Tert-Butyl 5 (1H) -carboxylate (CAS Number 370882-39-6) (0.181 g, 0.852 mmol) at rt. The reaction mixture was heated at 130 ° C for 8 h. The resulting reaction mixture was cooled to rt and poured into water (100 ml). The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated citric acid (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (43% EtOAc in hexane) yielding (3aR, 6aR) -1 - ((4-chloro-2-fluorophenyl) carbamoyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H ) -tert-butyl carboxylate (0.097 g, 0.252 mmol). LCMS: Method C, 2.263, MS: ES-382.59.
[1408] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that of described for steps b, c of Example 5 to provide the title compound. LCMS: Method B, RT 3.59 min, MS: ES + 309.42; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.15 (s, 1H), 7.52 (t, J = 8.8 Hz, 1H), 7.42 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 7.20-7.23 (m, 1H), 4.31-4.34 (m, 1H), 3.50-3.57 (m, 4 H), 3.39-3.42 (m, 1H), 3.23-3.27 (m, 1H), 2.93-2.98 (m, 1H), 2.01-2 .08 (m, 1H), 1.79-1.84 (m, 1H).
[1410] The compounds in Table 10 were synthesized using a procedure similar to general method E as illustrated by Example 5, Example 89, or Example 196.
[1411]
[1412] Example 204 ( R) -] - ( 1-cyanopyrrolidin-3-yl) -1-ethyl-3- ( 4- ( trifluoromethyl) phenyl) urea
[1414]
[1417] Stage a. To a solution of tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol) in DCM (2.5 ml) was added TEA (1.8 ml, 13.3 mmol ) at 0 ° C followed by mesyl chloride (0.62 ml, 8.01 mmol). The reaction mixture was stirred at rt for 1.5 h. The resulting mixture was concentrated under reduced pressure to yield tert-butyl (S) -3 - ((methylsulfonyl) oxy) pyrrolidine-1-carboxylate (1.5 g, quantitative). This substance was used directly for the next step without further purification. LCMS: Method C, RT 2.05 min, MS: ES + 266.2
[1419] Stage b. A mixture of tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate (0.5 g, 1.88 mmol) in aqueous ethylamine (70% in water) (10 ml) was heated at 90 ° C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue obtained was azeotroped with diethyl ether (3 x 5 ml) and dried under high vacuum to yield tert-butyl (R) -3- (ethylamino) pyrrolidine-1-carboxylate (0.3 g, 1.39 mmol). LCMS: Method C, RT 1.54 min, MS: ES + 215.29
[1420] Stages c-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-d of Example 194 to provide the title compound. LCMS: Method A, RT 4.42 min, MS: ES + 327.15; 1H NMR (400 MHz, DMSO-de) or ppm 8.67 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 4.61-4.65 (m, 1H), 3.52-3.57 (m, 2H), 3.31-3.43 (m, 3H), 3, 26-3.31 (m, 1H), 2.00-2.08 (m, 2H), 1.08 (t, J1 = 6.8, 3H).
[1422] Example 205 1- ( 1-cyanopyrrolidin-3-yl) -1- ( 2-methoxyethyl) -3- ( 4- ( trifluoromethyl) phenyl) urea
[1424]
[1427] Synthesized by a procedure similar to that described for Example 89 using tert-butyl 3 - ((2-methoxyethyl) amino) pyrrolidine-1-carboxylate (CAS number 887587-33-9) in step a. LCMS: Method A, RT 4.66 min, MS: ES + 357.03; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.91 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.83-4.87 (m, 1H), 3.57-3.79 (m, 4H), 3.56 (s, 3H), 3.37-3, 53 (m, 3H), 3.28-3.32 (m, 1H), 2.19-2.25 (m, 1H), 1.97-2.05 (m, 1H).
[1429] Example 206 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -N-ethyl-3-fluoro-4- ( 1-methyl-1H-pyrazol-4-yl) benzamide
[1431]
[1434] Synthesized by a procedure similar to that described for Example 63 using tert-butyl (R) -3- (ethylamino) pyrrolidine-1-carboxylate (described in the synthesis of Example 204) in step b. LCMS: Method A, RT 3.53 min, MS: ES + 342.06; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.19 (d, J = 2.0 Hz, 1H), 7.94 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 11.6, 1.6 Hz, 1H), 7.21 (dd, J = 8.0, 1.6 Hz, 1H), 4, 39-4.43 (m, 1H), 3.90 (s, 3H), 3.51-3.59 (m, 2H),
[1435] 3.41-3.47 (m, 2H), 3.28-3.33 (m, 2H), 2.01-2.15 (m, 2H), 1.04-1.10 ( m, 3H).
[1437] Example 207 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -N-ethyl-3-phenylazetidine-1-carboxamide
[1439]
[1442] Synthesized by a procedure similar to that described for Example 189 using tert-butyl (R) -3- (ethylamino) pyrrolidine-1-carboxylate (described in the synthesis of Example 204) in step c. LCMS: Method A, RT 4.07 min, MS: ES + 299.08; 1H NMR (400MHz, CDCh) 5 ppm 7.33-7.41 (m, 4H), 7.29-7.31 (m, 1H), 4.38-4.46 (m, 3H ), 4.02 -4.06 (m, 2H), 3.77-3.81 (m, 1H), 3.58-3.64 (m, 2H), 3.36-3, 47 (m, 2H), 3.17-3.20 (m, 2H), 2.11-2.15 (m, 2H), 1.18-1.21 (m, 3H).
[1443] Example 208 ( R) -3- ( 2-oxo-3- ( 4-phenylthiazol-2-yl) imidazolidin-1-yl) pyrrolidine-1-carbonitrile
[1445]
[1448] Stage a. To a stirred solution of (R) -3-amino-1N-BOC-pyrrolidine (1.0 g, 5.376 mmol) and DIPEA (1.04 g, 8.06 mmol) in THF (15 mL) was added triphosgene (0.526 g, 1.774 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h. 4-Phenylthiazol-2-amine (0.95 g, 5.376 mmol) was added to the reaction mixture at rt. The reaction mixture was heated at 60 ° C for 16 h. The resulting reaction mixture was cooled to rt, rapidly poured into water (50 ml), and extracted with EtOAc (2 x 20 ml). The combined organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl (R) -3- (3- (4-phenylthiazol-2-yl) ureido) pyrrolidine-1-carboxylate. (1.0 g, 2.58 mmol). This substance was used directly for the next step without further purification. LCMS: Method C, RT 2.51 min, MS: ES + 389.4
[1450] Stage b. To a stirred solution of tert-butyl (R) -3- (3- (4-phenylthiazol-2-yl) ureido) pyrrolidin-1-carboxylate (0.5 g, 1.29 mmol) in DMF (10 mL ) K ² CO ³ (0.71 g, 5.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min before adding 1,2-dibromoethane (0.29 g, 1.55 mmol). The reaction mixture was heated at 100 ° C for 2 h. The resulting reaction mixture was cooled to rt, rapidly poured into water (50 ml), and extracted with EtOAc (2 x 20 ml). The combined organic phase was separated, dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (35% EtOAc in hexane) yielding (R) -3- (2-oxo-3- (4-phenylthiazol-2-yl) imidazolidin-1-yl) pyrrolidin-1 - tert-butyl carboxylate (0.07 g, 0.169 mmol). LCMS: Method C, RT 2.80 min, MS: ES + 415.4
[1452] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 5 to provide the title compound. LCMS: Method B, RT 4.47 min, MS: ES + 340.28; 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.89 (d, J = 7.2 Hz, 2H), 7.56 (s, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 4.90-4.52 (m, 1H), 4.07-4.12 (m, 2H) , 3.61-3.65 (m, 2H), 3.41-3.58 (m, 4H), 2.05-2.13 (m, 2H).
[1454] Example 209 ( R) -3- ( 2-oxo-3- ( 4-phenylthiazol-2-yl) tetrahydropyrimidin-1 ( 2H) -yl) pyrrolidine-1-carbonitrile
[1456]
[1459] Stage a. To a stirred solution of (R) -3-amino-1 N-BOC-pyrrolidine (1.0 g, 5.37 mmol) in THF (12 mL) was added 2-chloroethyl isocyanate (CAS Number 1943-83 -5) (0.57 g, 5.37 mmol) at 0 ° C. The reaction mixture was stirred at rt for 1.5 h. NaH (60% dispersion in paraffin oil, 0.645 g, 16.12 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was heated at 50 ° C for 16 h. The resulting reaction mixture was cooled to rt, rapidly poured into water (50 ml), and extracted with EtOAc (4 x 50 ml). The combined organic phase was separated, dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using (8-9% MeOH in DCM) yielding tert-butyl (R) -3- (2-oxoimidazolidin-1-yl) pyrrolidine-1-carboxylate (1.03 g, 4,062 mmol). LCMS: Method C, RT 1.67 min, m S: ES + 256.32
[1461] Stage b. To a stirred solution of tert-butyl (R) -3- (2-oxoimidazolidin-1-yl) pyrrolidine-1-carboxylate (0.2 g, 0.829 mmol) and 4- (3-bromophenyl) morpholine (CAS number 197846-82-5) (0.21 g, 0.83 mmol) in toluene (7 mL) was added Cs2CO3 (0.81 g, 2.49 mmol) at rt. The reaction mixture was degassed for 30 min before the addition of Pd (OAc) ² (0.019 g, 0.083 mmol) and BINAP (0.103 g, 0.166 mmol). The reaction mixture was heated to 90 ° C for 10 h. The resulting reaction mixture was cooled and combined with two other batches prepared on the same scale by an identical method. The excess solvent was distilled off in vacuo and the resulting residue was purified by flash chromatography (54% EtOAc in hexane) yielding (R) -3- (3- (3-morpholinophenyl) -2-oxoimidazolidin-1-yl) pyrrolidine Tert-Butyl -1-carboxylate (0.267 g, 0.461 mmol). LCMS: Method C, RT 2.22 min, MS: ES + 417.70
[1462] Stages c, d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 5 to provide the title compound. LCMS: Method B, RT 3.33 min, MS: ES + 342.58; 1H NMR (400 MHz, DMSO-ds) 5 ppm 7.23 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 6.61 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 4.42 - 4.49 (m, 1H), 3.72 - 3.81 (m, 6H), 3.34-3.56 (m, 6H), 3.07 (t, J = 6.8 Hz, 4H), 1.97-2.12 ( m, 2H).
[1464] Example 211 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -4- ( pyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxamide
[1466]
[1469] Stage a. To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxylate (CAS number 142166-00-5) (0.7 g, 3, 38 mmol) in THF (14 ml) was added borane dimethyl sulfide complex (0.513 g, 6.76 mmol) at 0 ° C under nitrogen. The reaction mixture was heated at 60 ° C for 3 h. The reaction mixture was cooled to rt. MeOH (2 ml) was slowly added to the reaction mixture at 0 ° C and the resulting reaction mixture was heated at 60 ° C for 10 min. Excess solvent was distilled off in vacuo. The crude material was purified by flash chromatography. The resulting residue was purified by flash chromatography (20% EtOAc in hexane) yielding methyl 3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxylate (0.55 g, 2.85 mmol). LCMS: Method C, RT 1.96 min, MS: ES + 194.1
[1471] Stage b. To a stirred solution of methyl 3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxylate (0.44 g, 2.28 mmol) and 2-chloropyrimidine (0.782 g, 6, 83 mmol) in DMF (13.2 ml) was added Cs2CO3 (2.23 g, 6.83 mmol) at rt under nitrogen atmosphere. The reaction mixture was degassed for 15 min at rt before the addition of Pd2 (dba) 3 (0.021 g, 0.023 mmol) and xantphos (0.04 g, 0.683 mmol). The reaction mixture was heated to 140 ° C for 15 h. The resulting reaction mixture was cooled to rt, poured into water (100 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10% EtOAc in hexane) yielding 4- (pyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxylate of methyl (0.29 g, 1.07 mmol). LCm S: Method C, RT 2.25 min, MS: ES + 272.18
[1472] Stage c. To a stirred solution of methyl 4- (pyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxylate (0.29 g, 1.07 mmol) , (R) -3-amino-1N-BOC-pyrrolidine (0.22 g, 1.18 mmol) and DIPEA (0.276 g, 2.14 mmol) in THF (5.8 ml) was added 2M TMA in toluene (2.67 mL, 5.34 mmol) at 0 ° C. The reaction mixture was heated to 80 ° C for 2 h. The resulting reaction mixture was cooled to rt and quickly poured into a mixture of EtOAc: water (1: 1, 100 mL). The reaction mixture was filtered through a pad of celite, the organic phase was separated and the aqueous phase was re-extracted using EtOAc (2 x 25 ml). The combined organic phase was washed with brine (25 ml), separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (70% EtOAc in hexane) yielding (R) -3- (4- (pyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1, Tert-Butyl 4] oxazine-7-carboxamido) pyrrolidine-1-carboxylate (0.28 g, 0.66 mmol). LCMS: Method C, RT 2.19 min, MS: ES + 426.28
[1474] Stages d, e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps d, e of Example 2 to provide the title compound. LCMS: Method A, RT 3.38 min, MS: ES + 351.11; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.58 (d, J = 4.4 Hz, 2H), 8.47 (d, J = 6.4 Hz, 1H), 8.13 ( d, J = 8.4 Hz, 1H), 7.37-7.43 (m, 2H), 6.99 (t, J = 4.8 Hz, 1H), 4.43-4, 47 (m, 1H), 4.30-4.32 (m, 2H), 4.20-4.22 (m, 2H), 3.60-3.64 (m, 1H), 3.52-3.56 (m, 1H), 3.42-3.47 (m, 1H), 3.28-3.32 (m, 1H), 2.08-2.13 ( m, 1H), 1.93-1.96 (m, 1H).
[1475] Example 212 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -4- ( 4-cyclopropylpyrim idin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin- 7-carboxamide
[1477]
[1480] Stage a. To a stirred solution of 2,4-dichloropyrimidine (4.0 g, 26.85 mmol) and cyclopropylboronic acid (2.54 g, 29.54 mmol) in THF (80 ml) was added K ³ PO ⁴ (14.25 g, 67.13 mmol) at rt. The reaction mixture was degassed for 15 min at rt before the addition of Pd (dppf) Cl ² (1.965 g, 2.68 mmol). The reaction mixture was heated at 90 ° C for 2 h. The reaction mixture was cooled to rt, rapidly poured into water (150 ml) and extracted using EtOAc (3 x 100 ml). The combined organic phase was washed with brine (100 ml), separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in hexane) yielding 2-chloro-4-cyclopropylpyrimidine (1.0 g, 6.47 mmol). LCMS: Method C, RT 2.01 min, MS: ES + 155.15
[1482] Stages b-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-e of Example 211 to provide the title compound. LCMS: Method A, RT 4.22 min, MS: ES + 391.16; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.45 (d, J = 6.8 Hz, 1H), 8.35 (d, J = 4.8 Hz, 1H), 8.10 ( d, J = 8.4 Hz, 1H), 7.37-7.41 (m, 2H), 6.94 (d, J = 5.2 Hz, 1H), 4.44-4, 46 (m, 1H), 4.27-4.29 (m, 2H), 4.15-4.18 (m, 2H), 3.60-3.64 (m, 1H), 3.52-3.56 (m, 1H), 3.41-3.47 (m, 1H), 3.28-3.31 (m, 1H), 2.03-2.13 ( m, 2H), 1.93-1.97 (m, 1H), 1.00 (s, 4H).
[1484] Example 213 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -4- (( 4-cyclopropylpyrim idin-2-yl) amino) -3-fluorobenzamide
[1486]
[1489] Synthesized by a procedure similar to that described for Example 91 using 2-chloro-4-cyclopropylpyrimidine (as described for Example 212) in step b. LCMS: Method B, RT 3.90 min, MS: ES + 367.23; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.06 (s, 1H), 8.54 (d, J = 6.4 Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 8.8Hz, 1H),
[1490] 7.68 - 7.72 (m, 2H), 6.88 (d, J = 5.2 Hz, 1H), 4.45 - 4.49 (m, 1H), 3.62-3 , 66 (m, 1H), 3.53-3.59 (m, 1H), 3.42-3.48 (m, 1H), 3.30-3.31 (m, 1H) , 2.10-2.15 (m, 1H), 1.92-2.03 (m, 2H), 1.01-1.03 (m, 4H).
[1492] Example 214 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -4- (( 4-cyclopropylpyrim idin-2-yl) amino) -2,3-difluorobenzamide
[1494]
[1497] Synthesized by a procedure similar to that described for Example 91 using 2-chloro-4-cyclopropylpyrimidine (as described for Example 212) in step b. LCMS: Method A, RT 4.12 min, MS: ES + 385.11; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.35 (s, 1H), 8.65 (d, J = 6.4 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.70-7.74 (m, 1H), 7.33-7.37 (m, 1H), 6.89 (d, J = 5.2 Hz, 1H) , 4.43-4.47 (m, 1H), 3.61-3.65 (m, 1H), 3.43-3.55 (m, 2H), 3.27-3.31 (m, 1H), 2.08-2.14 (m, 1H), 1.89-2.04 (m, 2H), 0.97-1.05 (m, 4H).
[1499] Example 215 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -4- ( N-methylisobutyramido) picolinamide
[1501]
[1504] Stages a, b. Following a procedure similar to that described for steps a, b of Example 62, using methyl 4-aminopicolinate (CAS number 71469-93-7) in step a, to provide methyl 4- (N-methylisobutyramido) picolinate. LCMS: Method C, RT 1.72 min, MS: ES + 237.00. This substance was used directly for the next step without further purification.
[1506] Stage c. To a solution of methyl 4- (N-methylisobutyramido) picolinate (0.150 g, 0.635 mmol) in THF (10 ml) was added DIPEA (0.06 ml, 0.317 mmol) at rt. The reaction mixture was cooled to 0 ° C. Trimethylaluminum solution (2M in toluene) (1.5 ml, 3.177 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 ° C for 30 min and then treated with (R) -3-amino-1 N-BOC-pyrrolidine (0.118 g, 0.633 mmol). The reaction mixture was heated at 90 ° C for 2 h. The resulting reaction mixture was cooled to rt and poured into a saturated aqueous NaHCO3 solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl (R) -3- (4- (N-methylisobutyramido) picolinamido) pyrrolidine-1-carboxylate (0.220 g, 0.564 mmol) . LCMS: Method C, RT 2.097 min, MS: ES + 391.50. This substance was used directly for the next step without further purification.
[1508] Stages d, e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1. LCMS: Method B, RT 3.07 min, MS: ES + 316.10; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.08 (d, J = 6.4 Hz, 1H), 8.66 (d, J = 5.4 Hz, 1H), 7.97 ( d, J = 1.6 Hz, 1H), 7.62-7.64 (m, 1H),
[1509] 4.51 - 4.55 (m, 1H), 3.50-3.63 (m, 2H), 3.38-3.47 (m, 2H), 3.30 (s, 3H ), 2.74-2.78 (m, 1H), 1.99-2.16 (m, 2H), 1.01 (d, J = 6.4Hz, 6H).
[1510] Example 216 ( R) -N- ( 1-cyanopyrrolidin-3-yl) - [2,3'-bipyridine] -6'-carboxamide
[1512]
[1515] Stage a. To a solution of methyl 5-bromopicolinate (CAS Number 29682-15-3) (0.500 g, 2.314 mmol) in 1,4-dioxane (10 mL) was added 2- (tributylstanil) pyridine (CAS Number 17997-47 -6) (1.00 g, 2.717 mmol) at rt. The reaction mixture was degassed for 10 min before the addition of Pd (PPh3) 4 (0.132 g, 0.114 mmol). The reaction mixture was heated at 110 ° C for 16 h. The resulting reaction mixture was poured into water (70 ml) and extracted with EtOAc (2 x 70 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield methyl [2,3'-bipyridine] -6'-carboxylate (0.300 g, 1.401 mmol). LCMS: Method C, RT 1.75 min, MS: ES + 215.19. This substance was used directly for the next step without further purification.
[1517] Stages be. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps be of Example 2. LC ^m S: Method C, RT 1.76 min, MS: ES + 294.32; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.33 - 9.34 (m, 1H), 9.13 (d, J = 7.2 Hz, 1H), 8.75 - 8.77 (m, 1H), 8.64 (dd, J = 8.0, 2.0 Hz, 1H), 8.14-8.17 (m, 2H), 7.96-8.01 ( m, 1H), 7.47-7.50 (m, 1H), 4.54-4.58 (m, 1H), 3.55-3.65 (m, 2H), 3, 40-3.48 (m, 2H), 2.03-2.17 (m, 2H).
[1519] Example 217 ( R) -N- ( 1-cyanopyrrolidin-3-yl) - [2,4'-bipyridine] -2'-carboxamide
[1521]
[1524] Synthesized by a procedure similar to that described for Example 216 using methyl 4-bromopicolinate (CAS number 29681-42-3) in step a. LCMS: Method B, RT 3.17 min, MS: ES + 294.33; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.11 (d, J = 3.2 Hz, 1H), 8.78 - 8.79 (m, 2H), 8.71 (d, J = 1.2 Hz, 1H), 8.29 (dd, J = 5.2, 1.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7, 98-8.03 (m, 1H), 7.52-7.55 (m, 1H), 4.54-4.62 (m, 1H), 3.59-3.64 (m, 1H), 3.55-3.59 (m, 1H), 3.34-3.49 (m, 2H), 2.12-2.19 (m, 1H), 2.02 - 2.11 (m, 1H).
[1526] Example 218 ( R) -3- ( 4-chlorophenyl) -N- ( 1-cyanopyrrolidin-3-yl) isoxazole-5-carboxamide
[1528]
[1531] Stage a. To a solution of propiolic acid (0.800 g, 11.4 mmol) in THF (20 ml) was added DIPEA (6.00 ml, 35.1 mmol) and HATU (6,500 g, 17.105 mmol). The reaction mixture was stirred at rt for 30 min and then cooled to 0 ° C. The reaction mixture was treated with (R) -3-amino-1N-BOC-pyrrolidine (2.120 g, 11.4 mmol) and then stirred at rt for 15 h. The resulting reaction mixture was poured into saturated NaHCO3 solution (50 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl (R) -3-propriolamidopyrrolidine-1-carboxylate (2,200 g, 9, 24 mmol). LCMS: Method C, RT 1.88 min, MS: ES + 239.40. This substance was used directly for the next step without further purification.
[1533] Stage b. To a solution of 4-chlorobenzaldehyde (5,000 g, 35.5 mmol) in EtOH (50 mL) was added NH ² OH.HG (2,500 g, 36.0 mmol) at rt. A solution of NaOH (4,300 g, 407 mmol) in water (30 ml) was added to the reaction mixture at rt. The reaction mixture was refluxed for 2 h. The resulting reaction mixture was cooled to rt and acidified using a dilute HCl solution to adjust the pH ~ 3-4. The resulting precipitates were collected by filtration and washed with water (200 ml). The resulting solid substance was dissolved in EtOAc (100 ml) and washed with a saturated aqueous NaHCO3 solution (3 x 50 ml). The combined organic layer was washed with brine (2 x 70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding (E) -4-chlorobenzaldehyde oxime (4.6 g, 29.49 mmol). LCMS: Method C, RT 2.06 min, MS: ES 155.90; 1H NMR (400 MHz, DMSO-d6) 5 ppm 11.36 (s, 1H), 8.15 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7 , 45-7.52 (m, 2H). This substance was used directly for the next step without further purification.
[1534] Stages c, d. To a solution of (E) -4-chlorobenzaldehyde oxime (0.700 g, 4.49 mmol) in DCM (20 ml) was added N-chlorosuccinamide (0.900 g, 6.77 mmol) at 0 ° C. The reaction mixture was stirred at rt for 15 h. The reaction mixture was then cooled to 0 ° C. TEA (1.2 mL, 9.032 mmol) was added to the reaction mixture and stirred for 5 min. Tert-butyl (R) -3-propriolamidopyrrolidine-1-carboxylate (1,300 g, 5.46 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 15 h. The resulting reaction mixture was poured into water (100 ml) and extracted with DCM (3 x 30 ml). The combined organic layer was washed with brine (2 x 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (12-15% EtOAc in hexane) yielding tert-butyl (R) -3- (3- (4-chlorophenyl) isoxazole-5-carboxamido) pyrrolidine-1-carboxylate (0.400 g, 1.023 mmol). LCMS: Method C, RT 2.51 min, MS: ES-390.70.
[1535] Stages e, f. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1. LCMS: Method A, RT 4.30 min, MS: ES + 316.91; 1H NMR (400 MHz, DMSO-d6) or ppm 9.30 (d, J = 6.8 Hz, 1H), 7.95 - 7.98 (m, 2H), 7.71 (s, 1 H), 7.61-7.64 (m, 2H), 4.46-4.53 (m, 1H), 3.63-3.67 (m, 1H), 3.53-3 , 59 (m, 1H), 3.43-3.49 (m, 1H), 3.34-3.38 (m, 1H), 2.10-2.19 (m, 1H) , 1.94-2.02 (m, 1H). Example 219 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( 4- ( trifluoromethyl) phenyl) isoxazole-5-carboxamide
[1537]
[1539] Stage a. To a solution of 2-methylene succinic acid (CAS Number 97-65-4) (5000 g, 38.5 mmol) in water (70 ml) was added aniline (3000 g, 32.3 mmol) at rt. The reaction mixture was heated at 110 ° C for 30 h. The resulting reaction mixture was allowed to cool to rt and made alkaline using a 1M NaOH solution (100 ml). The obtained mixture was stirred for 10 min at rt. The resulting precipitates were filtered and the resulting filtrate was acidified using concentrated HCl. The precipitates obtained were collected by filtration and air dried yielding 5-oxo-1-phenylpyrrolidine-3-carboxylic acid (2,000 g, 9.76 mmol). LCMS: Method C, RT 1.70 min, MS: ES + 206.18; 1H NMR (400MHz, DMSO-de) 5 ppm 12.78 (s, 1H), 7.63-7.66 (m, 2H), 7.36-7.40 (m, 2H), 7.15 (t, J = 7.2 Hz, 1H), 4.03-4.08 (m, 1H), 3.95-3.99 (m, 1H), 3.32-3 , 39 (m, 1H), 2.67-2.82 (m, 2H).
[1540] Stage b. To a solution of 5-oxo-1-phenylpyrrolidine-3-carboxylic acid (1,000 g, 4.88 mmol) in MeOH (10 ml) was slowly added SOCl ² (0.658 g, 5.82 mmol) at 0 ° C for a period of 30 min. The reaction mixture was stirred at rt for 1 h. The resulting reaction mixture was concentrated under reduced pressure yielding methyl 5-oxo-1-phenylpyrrolidine-3-carboxylate (0.900 g, 4.11 mmol). LCMS: Method C, 1.90 min, MS: e S + 220.50. This substance was used directly for the next step without further purification.
[1542] Stage c. To a solution of 5-oxo-1-phenylpyrrolidine-3-carboxylate (1,500 g, 6.85 mmol) in THF (40 ml) was added 9-BBN (0.5 M in THF) (15 ml, 7, 50 mmol). The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was evaporated under reduced pressure and purified by flash chromatography (40% EtOAc in hexane) yielding methyl 1-phenylpyrrolidine-3-carboxylate (0.640 g, 3.12 mmol). LCMS: Method C, RT 2.44 min. MS: ES + 205.90.
[1544] Stages d-g. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-e of Example 2. LCMS: Method B, RT 3.55 min, MS: ES + 285.28; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.36 (d, J = 6.8 Hz, 1H), 7.15 (t, J = 8.4 Hz, 2H), 6.59 ( t, J = 7.2 Hz, 1H), 6.52 (d, J = 7.6 Hz, 2H), 4.23-4.27 (m, 1H), 3.37-3, 55 (m, 4H), 3.24-3.32 (m, 3H), 3.14-3.22 (m, 1H), 3.03-3.09 (m, 1H), 2.01-2.17 (m, 3H), 1.75-1.82 (m, 1H).
[1546] Example 223 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-fluoro-4- ( 4-methyl-1H-im idazol-1-yl) benzamide
[1548]
[1551] Stage a. To a solution of 3,4-difluorobenzaldehyde (1,000 g, 7.04 mmol) in DMF (10 ml) was added 4-methyl-1 H-imidazole (0.580 g, 7.07 mmol) and K ² CO ³ ( 1,200 g, 8.70 mmol) at rt. The reaction mixture was heated at 110 ° C for 16 h. The resulting reaction mixture was cooled to rt and poured into a saturated aqueous NaHCO ³ solution (150 ml). The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (30-50% EtOAc in hexane) yielding 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzaldehyde (1,300 g, 6.37 mmol). LCMS: Method C, RT 1.38 min, MS: ES + 205.19; 1H NMR (400 MHz, DMSO-de) 5 ppm 10.02 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7 , 89-7.92 (m, 2H), 7.40 (s, 1H), 2.18 (s, 3H).
[1553] Stage b. To a solution of 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzaldehyde (1,300 g, 6.37 mmol) in MeOH: water (7: 1, 16 ml) was added KOH ( 1.420 g, 25.36 mmol) at rt. The reaction mixture was heated to 65 ° C. ^{A solution of H 2} O ² (30% w / w in water) (5.60 ml, 49.41 mmol) was slowly added to the reaction mixture at 65 ° C and stirred for 16 h. The resulting reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting mixture was poured into water (200 ml), acidified using a 1M HCl solution and extracted with EtOAc (100 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 3-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzaldehyde (0.550 g, 2.50 mmol). LCMS: Method C, RT 1.25 min, MS: ES + 221.19. This substance was used directly for the next step without further purification.
[1555] Stages c-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 1. LCMS: Method A, RT 3.12 min, MS: ES + 313.98; 1H NMR (400MHz, DMSO-d6) 5 ppm 8.78 (d, J = 6.8 Hz, 1H), 8.01 (s, 1H), 7.92-7.96 (dd, J = 12.0, 1.6 Hz, 1H), 7.83-7.85 (m, 1H), 7.74-7.78 (m, 1H), 7.36 (s, 1H ), 4.47-4.50 (m, 1H), 3.63-3.67 (m, 1H), 3.53-3.59 (m, 1H), 3.45-3, 49 (m, 1H), 3.32-3.33 (m, 1H), 2.18 (s, 3H), 2.08-2.16 (m, 1H), 1.93 - 2.00 (m, 1H).
[1557] Example 224 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-fluoro-N-methyl-4- ( 4-methyl-1H-imidazol-1-yl) benzamide
[1559]
[1562] Synthesized by a procedure similar to that described for Example 223 using 1-N-BOC- (3R) -3- (methylamino) pyrrolidine in step c. LCMS: Method A, RT 3.10 min, MS: ES + 328.02; 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.97 (s, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.55 - 7.62 (m, 1 H), 7.34-7.42 (m, 1H), 7.32 (s, 1H), 4.32-4.37 (m, 1H), 3.52-3.54 (m , 2H), 3.44-3.47 (m, 2H), 2.89 (s, 3H), 2.18 (s, 3H), 2.02-2.09 (m, 2 H).
[1563] Example 225 N- (( R) -1-cyanopyrrolidin-3-yl) -3- ( pyridin-2-yl) pyrrolidine-1-carboxamide
[1565]
[1568] Stage a. To a solution of 2-vinylpyridine (CAS number 100-69-6) (5,000 g, 47.62 mmol) in DCM (30 ml) was added TFA (0.542 g, 4.75 mmol). The reaction mixture was stirred at rt for 5 min and then treated dropwise with a solution of N-benzyl-1-methoxy-N - ((trimethylsilyl) methyl) methanamine (CAS number 93102-05-7) (16 , 92 g, 71.39 mmol) in DCM (30 ml) over a period of 45 min. The reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into a saturated aqueous NaHCO3 solution (250 ml) and extracted with DCM (3 x 100 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 2- (1 -benzylpyrrolidin-3-yl) pyridine (8.00 g, 33.61 mmol). LCMS: Method C, RT 1.52 min, MS: ES + 239.25. This substance was used directly for the next step without further purification.
[1570] Stage b. To a solution of 2- (1-benzylpyrrolidin-3-yl) pyridine (5.00 g, 21.01 mmol) in EtOH (50 mL) was added 20% Pd (OH) 2 on carbon (50% of moisture content) (2.50 g) at rt. Polymethylhydroxylsilane (5.00 ml) was added to the reaction mixture at rt over a period of 10 min. The resulting reaction mixture was stirred at rt for 1 hr before the addition of BOC anhydride (9.150 g, 41.97 mmol). The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was filtered through a pad of celite and washed with MeOH (50 ml). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (10% EtOAc in hexane) yielding tert-butyl 3- (pyridin-2-yl) pyrrolidine-1-carboxylate (2.50 g, 10.08 mmol). LCMS: Method C, RT 1.84 min, MS: ES + 249.40.
[1572] Stage c. To a solution of tert-butyl 3- (pyridin-2-yl) pyrrolidin-1-carboxylate (0.500 g, 2.016 mmol) in DCM (4 ml) was added TFA (0.459 g, 4.03 mmol) at rt . The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was evaporated under reduced pressure. The resulting residue was co-evaporated with DCM (3x10 mL) and dried under high vacuum yielding 2- (pyrrolidin-3-yl) pyridine TFA salt (0.260 g, 0.984 mmol). MS: ES + 149.0. This substance was used directly for the next step without further purification.
[1574] Stages d-f. The title compound was synthesized from the above intermediate using a similar procedure to that described for Example 5. LCMS: Method A, RT 2.84 min, MS: ES + 285.98; 1H NMR (400 MHz, DMSO-d6) or ppm 8.51 (d, J = 4.0 Hz, 1H), 7.72 - 7.77 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.24 - 7.27 (m, 1H), 6.24 (d, J = 6.4 Hz, 1H), 4.09 - 4.18 (m , 1H), 3.68-3.73 (m, 1H), 3.47-3.57 (m, 4H), 3.36-3.45 (m, 1H), 3.27 - 3.31 (m, 1H), 3.16-3.19 (m, 2H), 2.19-2.25 (m, 1H), 1.95-2.11 (m, 2 H), 1.80-1.88 (m, 1H)).
[1576] Example 226 N- (( R) -1-cyanopyrrolidin-3-yl) -3- ( 1-methyl-1H-pyrazol-4-yl) pyrrolidine-1-carboxamide
[1578]
[1581] Synthesized by a procedure similar to that described for Example 5 using 1-methyl-4- (pyrrolidin-3-yl) -1H-pyrazole (CAS number 1211542-11-8) in step a. LCMS: Method H, rT 13.27 min, MS: ES + 289.07; 1H NMR (400 MHz, DMSO-de) 5 ppm 7.54 (s, 1H), 7.31 (s, 1H), 6.18 (d, J = 6.4 Hz, 1H), 4 , 11-4.14 (m, 1H), 3.78 (s, 3H), 3.60-3.64 (m, 1H), 3.45-3.52 (m, 2H) , 3.36-3.41 (m, 2H), 3.21-3.28 (m, 1H), 3.15-3.18 (m, 2H), 3.04-3.08 (m, 1H), 2.12-2.14 (m, 1H), 1.95-2.02 (m, 1H), 1.77-1.87 (m, 2H).
[1583] Example 227 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( 2-methoxypyridin-4-yl) -N-methylisoxazole-5-carboxamide
[1585]
[1588] Stage a. To a solution of 2-methoxyisonicotinaldehyde (CAS number 72716-87-1) (0.500 g, 3.65 mmol) in MeOH (7 ml) was added NH2OH.HG (0.503 g, 7.29 mmol) at rt. The reaction mixture was heated to 70 ° C for 1 hr. The resulting reaction mixture was concentrated under reduced pressure yielding (E) -2-methoxyisonicotinaldehyde oxime (1.20 g, quantitative). LCMS: Method A, RT 2.54 min, MS: ES + 152.91. This substance was used directly for the next step without further purification.
[1590] Stage b. To an oxime solution of (E) -2-methoxyisonicotinaldehyde (0.600 g, 3.95 mmol) in DMF (7 ml) was added N-chlorosuccinamide (0.787 g, 5.92 mmol) at 0 ° C. The reaction mixture was stirred at rt for 3 h. They were added 1,8-diazabicyclo [5.4.0] undec-7-ene (0.900 g, 5.92 mmol) and methyl propriolate (0.500 g, 5.95 mmol) to the reaction mixture and stirred at rt for 16 h. The resulting mixture was poured into cold water (150 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (70% EtOAc in hexane) yielding methyl 3- (2-methoxypyridin-4-yl) isoxazole-5-carboxylate (0.330 g, 1.410 mmol). LCMS: Method C, RT 2.17 min, MS: ES + 235.25.
[1591] Stages c-f. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-e of Example 2. LCMS: Method A, RT 3.68 min, MS: ES + 328.02; 1H NMR (400 MHz, DMSO-de, 80 ° C) 5 ppm 8.34 (d, J = 5.2 Hz, 1H), 7.59 (s, 1H), 7.50 (dd, J = 5.6, 1.6 Hz, 1H), 7.34 (s, 1H), 4.50-5.10 (m, 1H), 3.94 (s, 3H), 3, 56-3.65 (m, 2H), 3.41-3.51 (m, 2H), 3.04 (s, 3H), 2.10-2.23 (m, 2H).
[1592] Example 228 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -2-fluoro-4- ( N-methylphenylsulfonamido) benzamide
[1594]
[1596] Stage a. A mixture of methyl 4-amino-2-fluorobenzoate (0.300 g, 1.77 mmol) and ethyl formate (10 ml) was heated at 80 ° C for 16 h. The resulting reaction mixture was cooled to rt and concentrated under reduced pressure yielding methyl 2-fluoro-4-formamidobenzoate (0.332 g, 1.685 mmol). LCMS: Method C, Rt 1.79 min, MS: ES-196.12.
[1597] Stage b. To a solution of methyl 2-fluoro-4-formamidobenzoate (0.332 g, 1.68 mmol) in THF (5 ml) was added a 1 M solution of BH3.THF complex in THF (8.42 ml, 8 , 43 mmol) at 0 ° C. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was cooled to 0 ° C and acidified with 10% HCl in MeOH (5 ml). The reaction mixture was heated to 50 ° C for 1 hr. The resulting reaction mixture was cooled to 0 ° C and made alkaline using a saturated aqueous NaHCO3 solution. The resulting reaction mixture was concentrated under reduced pressure. The residue obtained was poured into water (30 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure yielding methyl 2-fluoro-4- (methylamino) benzoate (0.331 g, quantitative). lCm S: Method C, RT 2.031 min. MS: ES + 184.06. This substance was used directly for the next step without further purification.
[1598] Stage c. To a solution of methyl 2-fluoro-4- (methylamino) benzoate (0.331 g, 1.81 mmol) in pyridine (3 ml) was added benzenesulfonyl chloride (0.383 g, 2.17 mmol) at 0 ° C and stirred for 1 hr. The resulting reaction mixture was poured into a saturated aqueous citric acid solution (20 ml) and extracted with EtOAc (30 ml). The organic layer was washed with a saturated aqueous citric acid solution (2 x 20 ml). The organic layer was washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure yielding methyl 2-fluoro-4- (N-methylphenylsulfonamido) benzoate (0.506 g, 1.56 mmol). LCMS: Method C, RT 2.36 min, MS: ES + 324.19. This substance was used directly for the next step without further purification.
[1599] Stages dg. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps be of Example 2. LCMS: Method A, RT 4.00 min, MS: ES + 402.94; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.68 (d, J = 6.4 Hz, 1H), 7.72 - 7.75 (m, 1H), 7.53 - 7.64 (m, 5H), 7.09-7.15 (m, 2H), 4.41-4.45 (m, 1H), 3.60-3.64 (m, 1H), 3 , 42-3.53 (m, 2H), 3.26-3.29 (m, 1H), 3.17 (s, 3H), 2.06-2.15 (m, 1H) , 1.87-1.93 (m, 1H). Example 229 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -1-methyl-6- ( 1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide
[1601]
[1603] Stage a. To a solution of 6-bromo-1 H-indole-2-carboxylic acid (CAS number 16732-65-3) (0.249 g, 1.04 mmol) in THF (8 ml) were added DIPEA (0.402 g, 3.112 mmol) and HATU (0.394 g, 1.04 mmol) at rt. The reaction mixture was stirred at rt for 10 min. A solution of (R) -3-amino-1 N-BOC-pyrrolidine (CAS No. 147081 -49-0) (0.193 g, 1.03 mmol) in THF ( 2 ml). The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was poured into water (50 ml) and extracted with DCM (2 x 25 ml). The combined organic layer was washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (40% EtOAc in hexane) yielding tert-butyl (R) -3- (6-bromo-1H-indole-2-carboxamido) pyrrolidine-1-carboxylate (0.400 g, 0.980 mmol). LCMS: Method C, Rt 2.24 min, MS: ES + 408.50, 410.50.
[1605] Stage b. A solution of tert-butyl (R) -3- (6-bromo-1-methyl-1H-indole-2-carboxamido) pyrrolidine-1-carboxylate (0.460 g, 1.130 mmol) in DMF (10 mL) was Cs2CO3 (0.730 g, 2.239 mmol) and methyl iodide (0.320 g, 2.254 mmol) were added. The reaction mixture was heated at 100 ° C for 2.5 h. The resulting reaction mixture was cooled to rt and poured into water (150 ml). The resulting mixture was extracted with DCM (2 x 25 ml). The combined organic phase was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding (R) -3- (6-bromo-1-methyl-1H-indole-2-carboxamido) tert-Butyl pyrrolidine-1-carboxylate (0.400 g, 0.95 mmol). LCMS: Method C, RT 2.61 min, MS: ES + 422.30, 424.30. This substance was used directly for the next step without further purification.
[1607] Stages c-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-d of Example 3. LCMS: Method A, RT 3.56 min, MS: ES + 349.11; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.62 (d, J = 6.8 Hz, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7 , 72 (s, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.12 (s, 1 H), 4.47-4.50 (m, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.63-3.67 (m, 1H) , 3.56-3.58 (m, 1H), 3.43-3.47 (m, 2H), 2.11-2.14 (m, 1H), 1.96-1.97 (m, 1H).
[1609] Example 230 ( R) -N ( 1-cyanopyrrolidin-3-yl) -1-methyl-5- ( 1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide
[1611]
[1614] Synthesized by a procedure similar to that described for Example 229 using 5-bromoindole-2-carboxylic acid (CAS number 7254-19-5) in step a. LCMS: Method A, RT 3.56 min, MS: ES + 349.04; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.68 (d, J = 6.8 Hz, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7 , 79 (s, 1H), 7.48-7.53 (m, 2H), 7.11 (s, 1H), 4.46-4.50 (m, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.63-3.67 (m, 1H), 3.54-3.60 (m, 1H), 3.43-3 , 49 (m, 1H), 3.21-3.32 (m, 1H), 2.11-2.16 (m, 1H), 1.94-1.99 (m, 1H) .
[1616] Example 231 ( R) -1- ( 1-cyanopyrrolidin-3-yl) -3- ( 2- ( isoindolin-2-yl) pyridin-4-yl) -1-methylurea
[1618]
[1621] Stage a. Isoindoline (0.557 g, 4.68 mmol), potassium tert-butoxide (2.070 g, 9 , 76 mmol) and BINAP (0.243 g, 0.390 mmol) at rt. The reaction mixture was degassed for 5 min before the addition of Pd2 (dba) 3 (0.178 g, 0.194 mmol) at rt. The reaction mixture was heated to 110 ° C for 4 h. The resulting reaction mixture was cooled to rt and poured into water (200 ml). The resulting mixture was extracted with DCM (3 x 100 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (3% MeOH in DCM) yielding 2- (isoindolin-2-yl) pyridin-4-amine (0.700 g, 3.317 mmol). LCMS: Method C, Rt 1.68 min, MS: ES + 212.13.
[1623] Stages b-d. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-d of Example 194. LCMS: Method A, RT 3.83 min, MS: ES + 363.08; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.60 (s, 1H), 7.92 (d, J = 5.6 Hz, 1H), 7.39 - 7.42 (m, 2 H), 7.30-7.33 (m, 2H), 6.91 (d, J = 1.2 Hz, 1H), 6.82-6.84 (m, 1H), 4, 85-4.93 (m, 1H), 4.68 (s, 4H), 3.50-3.58 (m, 2H), 3.36-3.42 (m, 1H), 3.30-3.32 (m, 1H), 2.90 (s, 3H), 1.95-2.07 (m, 2H).
[1625] Example 232 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3-fluoro-1-methyl-5- ( 1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide
[1627]
[1630] Stage a. K2CO3 (0.521 g, 3.77 mmol) and methyl iodide (0.536 g, 3.77 mmol) at rt. The reaction mixture was heated at 100 ° C for 16 h. The resulting reaction mixture was cooled to rt and poured into water (50 ml). The resulting mixture was extracted with EtOAc (3 x 20 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate (0.426 g, 1.52 mmol). LCMS: Method C, RT 2.83 min, MS: ES + 282.10, 284.10. This substance was used directly for the next step without further purification.
[1631] Stage b. To a solution of ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate (0.200 g, 0.71 mmol) in 1,2-dichloroethane (10 ml) was added 1-fluoro-triflate. 2,4,6-trimethylpyridinium (CAS number 107264-00-6) (0.617 g, 2.13 mmol) at rt. The reaction mixture was heated at 100 ° C for 16 h. The resulting reaction mixture was cooled to rt and poured into water (30 ml). The resulting mixture was extracted with EtOAc (3 x 10 ml). The combined organic phase was washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (2% EtOAc in hexane) yielding ethyl 5-bromo-3-fluoro-1-methyl-1H-indole-2-carboxylate (0.135 g, 0.450 mmol). LCMS: Method C, RT 2.96 min, MS: ES + 300.20, 302.20.
[1632] Stages c-g. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 2. LCMS: Method A, RT 3.70 min, MS: ES + 367.07; 1H NMR (400 MHz, DMSO-d6) or ppm 8.64 (d, J = 6.0 Hz, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7 , 79 (s, 1H), 7.57-7.59 (m, 2H), 4.51-4.52 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.64-3.75 (m, 1H), 3.39-3.56 (m, 3H), 2.13-2.18 (m, 1H), 1 , 94-1.99 (m, 1H).
[1633] Example 233 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -7- ( 1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a] pyridine-3-carboxamide
[1635]
[1637] Stage a. To a solution of 4-bromopyridine-2-carbonitrile (CAS number 62150-45-2) (1.50 g, 8.20 mmol) in 1,4-dioxane: water (9: 1, 20 ml) was added 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.870 g, 8.99 mmol) and Cs2CO3 (8.010 g, 24, 57 mmol) at rt. The reaction mixture was degassed for 10 min before the addition of PdCl2 (dppf) (0.598 g, 0.816 mmol). The reaction mixture was heated at 80 ° C for 1 hr. The resulting reaction mixture was cooled to rt and poured into water (40 ml). The resulting mixture was extracted with EtOAc (3 x 75 ml). The combined organic phase was washed with brine (25 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with n-pentane (2 x 5 ml) and dried under high vacuum yielding 4- (1-methyl-1H-pyrazol-4-yl) picolinonitrile (2.090 g, 11.36 mmol). LCMS: Method C, RT 1.66 min, MS: ES + 185.19. This substance was used directly for the next step without further purification.
[1638] Stage b. To a solution of 4- (1-methyl-1H-pyrazol-4-yl) picolinonitrile (0.900 g, 4.891 mmol) in THF (40 ml) was added a 1 M solution of LiAlH4 in THF (4.88 ml , 4.891 mmol) at -5 ° C. The reaction mixture was stirred at rt for 1h. The reaction mixture was diluted with THF (50 ml), treated with Na2SO4-10H2O (15.00 g) and stirred for 20 min. The resulting reaction mixture was filtered and washed with DCM (50 ml). The combined filtrate was concentrated under reduced pressure. 4M HCl in 1,4-dioxane solution was added to the obtained residue to form the corresponding HCl salt. The precipitates obtained were collected by filtration under a nitrogen atmosphere and dried under high vacuum yielding the HCl salt of (4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) methanamine (1.28 g, quantitative). MS: ES + 189.12. This substance was used directly for the next step without further purification. Stage c. To a solution of HCl salt of (4- (1-methyl-1 H-pyrazol-4-yl) pyridin-2-yl) methanamine (0.500 g, 2.22 mmol) in DCM (30 ml) was added DIPEA (0.860 g, 6.65 mmol) at 0 ° C. A solution of ethyl chloroxoacetate (0.300 g, 2.20 mmol) in DCM (30 ml) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was poured into water (50 ml) and extracted with DCM (40 ml). The organic layer was washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure yielding 2 - (((4- (1-methyl-1H-pyrazol-4-yl) pyridin-2- ethyl yl) methyl) amino) -2-oxoacetate (0.540 g, 1.87 mmol). LCMS: Method F, RT 4.49 min, MS: ES + 289.10. This substance was used directly for the next step without further purification. Stage d. A mixture of ethyl 2 - (((4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) methyl) amino) -2-oxoacetate (0.540 g, 1.87 mmol) and P2O5 (1,320 g, 9.295 mmol) in POCh (11 ml) was heated at 80 ° C for 48 h. The resulting reaction mixture was cooled to room temperature and made alkaline with a saturated aqueous solution of Na2CO3. The obtained mixture was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine (40 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography (80% EtOAc in hexane) yielding ethyl 7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a] pyridine-3-carboxylate (0.070 g , 0.259 mmol). LCMS: Method C, RT 1.78 min, MS: ES + 271.40.
[1639] Stages huh. The title compound was synthesized from the above intermediate using a procedure similar to that of described for steps be of Example 2. LCMS: Method A, RT 3.22 min, MS: ES + 336.07; 1H NMR (400 MHz, DMSO-de) 5 ppm 9.32 (d, J = 7.2 Hz, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.28 ( s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.51 (s, 1H), 7.26 (d, J = 7.2 Hz, 1 H), 4.52-4.57 (m, 1H), 3.88 (s, 3H), 3.55-3.64 (m, 2H), 3.38-3.51 (m , 2H), 2.02-2.14 (m, 2H).
[1641] Example 234 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( 1-phenyl-1 H-pyrazol-3-yl) azetidine-1-carboxamide
[1643]
[1646] Stage a. To a solution of 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (CAS number 142253-55-2) (3.00 g, 14.92 mmol) in THF (30 ml) was added CDI (2, 70 g, 16.67 mmol) at 0 ° C. The reaction mixture was stirred at rt for 2 h. A solution of N, O-dimethylhydroxylamine hydrochloride (1.90 g, 19.48 mmol) in MeCN (45 ml) was added to the reaction mixture followed by the addition of TEA (3.10 ml, 22.39 mmol ). The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was concentrated under reduced pressure and poured into water (200 ml). The obtained mixture was extracted with EtOAc (3 x 50 ml). The combined organic layer was washed with a citric acid solution (100 ml) and brine (100 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl 3- (methoxy (methyl) carbamoyl) azetidine-1-carboxylate (3.40 g, 13.93 mmol). LCMS: Method C, RT 1.96 min, MS: ES + 245.20. This substance was used directly for the next step without further purification.
[1648] Stage b. A mixture of CH3MgBr (3M in diethyl ether) (9.25 ml, 27.75 mmol) in toluene: THF (7: 3, 48 ml) was cooled to 0 ° C. A solution of tert-butyl 3- (methoxy (methyl) carbamoyl) azetidine-1-carboxylate (3.40 g, 13.93 mmol) in THF (20 mL) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was quenched by slow addition of citric acid solution (50 ml). The resulting reaction mixture was extracted with EtOAc (3 x 50 ml). The combined organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure yielding tert-butyl 3-acetylazetidine-1-carboxylate (2.150 g, 10.80 mmol). LCMS: Method C, RT 1.98 min, MS: ES + 144.10 (M-56). This substance was used directly for the next step without further purification.
[1650] Stage c. A mixture of tert-butyl methyl 3-acetylazetidine-1-carboxylate (2.15 g, 10.80 mmol) in N, N-dimethylformamide dimethylacetal (16 ml, 120.6 mmol) was heated at 110 ° C for 16 h. The resulting reaction mixture was concentrated under reduced pressure and the obtained residue was purified by flash chromatography (80-100% EtOAc in hexane) yielding (E) -3- (3- (dimethylamino) acryloyl) azetidine-1-carboxylate of tert-butyl (1,900 g, 7.48 mmol). LCMS: Method C, RT 1.91 min, m S: ES + 255.20.
[1652] Stage d. To a solution of tert-butyl (E) -3- (3- (dimethylamino) acryloyl) azetidine-1-carboxylate (0.500 g, 1.97 mmol) in EtOH (6 ml) was added phenylhydrazine (0.280 g, 2.59 mmol) and acetic acid (0.05 ml). The reaction mixture was heated at 60 ° C for 4 h. The resulting reaction mixture was cooled to rt and concentrated under reduced pressure. The obtained crude substance was purified by flash chromatography to obtain tert-butyl 3- (1-phenyl-1H-pyrazol-3-yl) azetidine-1-carboxylate (47% EtOAc / hexane) (0.170 g, 0, 57 mmol) and tert-butyl 3- (1-phenyl-1H-pyrazol-5-yl) azetidine-1-carboxylate (70% EtOAc / hexane) (0.210 g, 0.70 mmol). The obtained tert-butyl 3- (1-phenyl-1H-pyrazol-3-yl) azetidine-1-carboxylate was used for the next step. LCMS: Method C, RT 2.58 min, MS: ES 300.30; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.46 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.8, 1.2 Hz, 2H), 7.49 (t, J = 5.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H) , 4.23 (t, J = 8.0 Hz, 2H), 3.89-3.96 (m, 2H), 3.85-3.89 (m, 1H), 1.40 ( s, 9H).
[1654] Stage e. A solution of tert-butyl 3- (1-phenyl-1H-pyrazol-3-yl) azetidine-1-carboxylate (0.270 g, 0.90 mmol) in 1,4-dioxane (5 ml) was added added 4M HCl in 1,4-dioxane (5 mL) at rt. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was concentrated under reduced pressure. The residue obtained was evaporated together with DCM (3 x 10 ml) and finally dried under high vacuum producing HCl salt of 3- (azetidin-3-yl) -1-phenyl-1 H-pyrazole (0.270 g, quantitative) . LCMS: Method C, RT 1.53 min, MS: ES +200.30. This substance was used directly for the next step without further purification.
[1656] Stages fh. The title compound was synthesized from the above intermediate using a similar procedure to that described for Example 89. LCMS: Method B, rT 3.54 min, MS: ES + 337.22; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.46 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.48 ( t, J = 8.0 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 6.54-6.57 (m, 2H), 4.13-4, 21 (m, 3H), 3.84-3.94 (m, 3H), 3.45-3.54 (m, 2H), 3.35-3.41 (m, 1H), 3.13-3.17 (m, 1H), 1.98-2.03 (m, 1H), 1.77-1.82 (m, 1H).
[1658] Example 235 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -3- ( 1- ( pyrazin-2-yl) -1H-pyrazol-3-yl) azetidine-1-carboxamide
[1660]
[1663] Stage a. To a solution of tert-butyl (E) -3- (3- (dimethylamino) acryloyl) azetidine-1-carboxylate (described in steps ac of Example 234) (0.900 g, 3.54 mmol) in MeOH (10 ml) NaOMe (0.480 g, 8.89 mmol) was added at rt. Benzamidine hydrochloride hydrate (0.700 g, 4.47 mmol) was added to the reaction mixture at rt. The reaction mixture was refluxed for 5 h. The resulting reaction mixture was cooled to rt and filtered through a pad of celite, washed with MeOH (10 ml). The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (25% EtOAc in hexane) yielding tert-butyl 3- (2-phenylpyrimidin-4-yl) azetidine-1-carboxylate (0.610 g, 1.96 mmol). LCMS: Method C, RT 2.55 min, MS: eS + 312.13; 1H NMR (400 MHz, DMSO-de) 5 ppm 8.83 (d, J = 5.2 Hz, 1H), 8.42 - 8.44 (m, 2H), 7.51 - 7.55 (m, 3H), 7.39 (d, J = 5.2 Hz, 1H), 4.23 -4.26 (m, 2H), 4.13-4.10 (m, 2H ), 3.96-4.01 (m, 1H), 1.42 (s, 9H).
[1665] Stages b-e. The title compound was synthesized using a procedure similar to that described for step e of Example 134, followed by steps a-c of Example 5. LCMS: Method A, RT 3.63 min, MS: ES + 349.04; 1H NMR (400MHz, DMSO-de) 5 ppm 8.83-8.84 (m, 1H), 8.41-8.44 (m, 2H), 7.52-7.56 (m, 3H), 7.32-7.40 (m, 1H), 6.63 (d, J = 6.4Hz, 1H), 4.17-4.24 (m, 3H), 3 , 98-4.10 (m, 3H), 3.46-3.55 (m, 2H), 3.34-3.42 (m, 1H), 3.15-3.17 (m , 1H), 1.99-2.04 (m, 1H), 1.81-1.84 (m, 1H).
[1667] Example 237 ( R) -3- ( 2- ( 4-chlorophenyl) pyrimidin-4-yl) -N- ( 1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide
[1669]
[1672] Stage a. To a solution of tert-butyl 3-hydroxy-3-phenylazetidine-1-carboxylate (1.00 g, 4.016 mmol) in DCM (50 ml) was added tetrabutylammonium bromide (0.129 g, 0.400 mmol) and a solution 4M NaOH (40 ml). Benzyl bromide (1.43 mL, 12.05 mmol) was added dropwise to the reaction mixture at rt. The reaction mixture was heated at 80 ° C for 16 h. The resulting reaction mixture was cooled to rt and poured into brine (50 ml). The resulting mixture was extracted with DCM (50 ml). The organic layer was washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure yielding tert-butyl 3- (benzyloxy) -3-phenylazetidine-1-carboxylate (1.80 g, quantitative ). LCMS: Method C, RT 2.88 min, MS: ES + 340.30. This substance was used directly for the next step without further purification.
[1673] Stage b. To a solution of tert-butyl 3- (benzyloxy) -3-phenylazetidine-1-carboxylate (1.80 g, 5.31 mmol) in DCM (50 mL) was added 4 M HCl in 1,4-dioxane (18 ml) at 0 ° C. The reaction mixture was stirred at rt for 1h. The resulting reaction mixture was concentrated under reduced pressure. The residue obtained was co-evaporated with DCM (3 x 50 ml). The material obtained was triturated with diethyl ether (3 x 40 ml) and finally dried under high vacuum yielding the HCl salt of 3- (benzyloxy) -3-phenylazetidine (1.17 g, 4.25 mmol). lCMS: Method C, RT 1.72 min, MS: ES + 240.23; 1H NMR (400MHz, DMSO-d6) or ppm 9.76 (s, 1H), 9.48 (s, 1H), 7.45 - 7.53 (m, 5H), 7.33 - 7.36 (m, 5H), 4.38 (s, 2H), 4.30 (s, 2H), 4.17 (s, 2H). This substance was used directly for the next step without further purification.
[1675] Stages c-e. The title compound was synthesized from the above intermediate using a similar procedure to that described for Example 89. LCMS: Method A, RT 4.41 min, MS: ES + 377.06; 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.45 - 7.51 (m, 4H), 7.26 - 7.40 (m, 6H), 6.69 (d, J = 6, 8 Hz, 1H), 4.20 (s, 2H), 4.14-4.17 (m, 1H), 4.13 (s, 4H), 3.44-3.53 (m , 2H), 3.35-3.41 (m, 1H), 3.13-3.16 (m, 1H), 1.98-2.03 (m, 1H), 1.76 - 1.81 (m, 1H).
[1677] Example 239 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -1- ( 4-cyclopropylpyrim idin-2-yl) indoline-5-carboxamide
[1679]
[1682] Stage a. To a solution of 2-chloro-4-cyclopropylpyrimidine (1.080 g, 7.01 mmol) in DMF (10 ml) was added methyl indoline-5-carboxylate (Ca S Number 339007-88-4) (1,000 g, 5.65 mmol) and Cs2CO3 (5.510 g, 16.90 mmol) at rt. The reaction mixture was degassed for 30 min before the addition of Xantphos (0.320 g, 0.553 mmol) and Pd2 (dba) 3 (0.250 g, 0.273 mmol) at rt. The reaction mixture was heated to 120 ° C for 4 h. The resulting reaction mixture was cooled to rt and poured into ice water (100 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layer was washed with ice water (25 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (25 ml) and dried under high vacuum yielding 2-chloro-4-cyclopropylpyrimidine (1.25 g, 4.21 mmol). LCMS: Method C, RT 2.81 min, MS: ES + 296.40; 1H NMR (400 MHz, CDCh) 5 ppm 8.31 - 8.35 (m, 2H), 7.89 (dd, J = 8.8, 8.8 Hz, 1H), 7.85 (s , 1H), 6.70 (d, J = 5.2Hz, 1H), 4.28 (t, J = 8.8Hz, 2H), 3.90 (s, 3H), 3 , 21 (t, J = 8.8 Hz, 2H), 1.94-1.98 (m, 1H), 1.23-1.28 (m, 2H), 1.11-1, 08 (m, 2H). This substance was used directly for the next step without further purification.
[1684] Stages b-e. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b-e of Example 2. LCMS: Method B, RT 4.13 min, MS: ES + 375.22; 1H NMR (400 MHz, CDCl3) 5 ppm 8.31 - 8.35 (m, 2H), 7.60 - 7.64 (m, 2H), 6.71 (d, J = 5.2 Hz , 1H), 6.16 (d, J = 6.8 Hz, 1H), 4.71-4.73 (m, 1H), 4.26-4.30 (m, 2H), 3.75-3.80 (m, 1H), 3.54-3.66 (m, 2H), 3.39-3.42 (m, 1H), 3.19-3.24 ( m, 2H),
[1685] 2.27-2.34 (m, 1H), 1.95-2.07 (m, 2H), 1.22-1.27 (m, 2H), 1.19-1.21 ( m, 2H).
[1687] Example 240 ( R) -N- ( 1-cyanopyrrolidin-3-yl) -1- ( 4-cyclopropylpyrimidin-2-yl) -N-methylindoline-5-carboxamide
[1689]
[1692] Stage a. To a solution of (2-methylpyridin-4-yl) boronic acid (CAS number 579476-63-4) (0.500 g, 3.65 mmol) and 3-bromoaniline (0.620 g, 3.60 mmol) in DMF: water (8: 2, 10 mL) was added Cs2CO3 (3.570 g, 10.95 mmol) at rt. The reaction mixture was degassed for 30 min before the addition of Pd (PPh3) 4 (0.420 g, 0.363 mmol) at rt. The reaction mixture was heated at 90 ° C for 16 h. The resulting reaction mixture was cooled to rt and poured into water (100 ml). The obtained mixture was extracted with EtOAc (2 x 100 ml). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (70% EtOAc in hexane) yielding 3- (2-methylpyridin-4-yl) aniline (0.450 g, 2.445 mmol). LCMS: Method C, Rt 0.97 min, MS: ES + 185.09
[1693] Stages b-d. The title compound was synthesized from the above intermediate using a similar procedure to that described for Example 89, using (3aR, 6aR) -5-N-BOC-hexahydro-pyrrolo [3,4-b] pyrrole (CAS number 370882 -39-6) in step b. LCMS: Method B, RT 2.57 min, m S: ES + 348.16; 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.49 (d, J = 5.6 Hz, 1H), 8.43 (s, 1H), 7.94 (s, 1H), 7 , 61-7.63 (m, 1H), 7.49 (s, 1H), 7.40-7.42 (m, 1H), 7.34-7.36 (m, 2H) ,
[1694] , 36-4.40 (m, 1H), 3.52-3.60 (m, 4H), 3.41-3.47 (m, 1H), 3.25-3.29 (m , 1H), 2.92-3.97 (m, 1H), 2.45 (s, 3H), 1.99-2.08 (m, 1H), 1.82-1.86 (m, 1H).
[1696] The compounds in Table 11 were synthesized using a procedure similar to that described for Example 241.
[1698]
[1701] Example 52 was further subjected to enantiomeric separation using preparative HPLC; mobile phase: (A) hexane (B) IPA: MeOH (50:50), column: CHIRa LpAK IC 250x21.0 mm, 5 pm, flow rate: 15 ml / min to provide the title compound. Lc Ms: Method A, RT 3.56 min, MS: ES + 308.06; Chiral HPLC: Method X, r T 14.99 min; 1H NMR (400 MHz, DMSO-de, 80 ° C) 5 ppm 13.51 (s, 1H), 7.80-7.84 (m, 2H), 7.44-7.48 (m, 2H), 7.37-7.38 (m, 1H), 7.06 (s, 1H), 4.61-5.10 (m, 1H), 3.70-3.98 ( m, 2H), 3.60-3.62 (m, 1H), 3.57-3.59 (m, 1H), 3.30-3.33 (m, 2H), 3, 02-3.10 (m, 1H), 2.06-2.08 (m, 1H), 1.87-1.88 (m, 1H).
[1702] Example 247 ( 3aR, 6aR) -1- ( 3-phenoxyazetidine-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 ( 1H) -carbonitrile
[1704]
[1706] Synthesized by a procedure similar to that described for Example 89, using (3aR, 6aR) -5-N-BOC-hexahydro-pyrrolo [3,4-b] pyrrole (CAS number 370882-39-6) in step a. lCm S: Method B, RT 3.53 min, MS: ES + 313.34; 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.30 (t, J = 8.4 Hz, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.83 ( d, J = 7.6 Hz, 2H), 4.98-5.01 (m, 1H), 4.40-4.44 (m, 1H), 4.25-4.29 (m , 2H), 3.90-3.94 (m, 1H), 3.78-3.82 (m, 1H), 3.49-3.54 (m, 2H), 3.34 - 3.40 (m, 3H), 3.18-3.22 (m, 1H), 2.85-2.87 (m, 1H), 1.88-1.95 (m, 1 H), 1.75-1.76 (m, 1H). Example 248 N- ( 1-cyanopiperidin-3-yl) - [1,1'-biphenyl] -3-carboxamide
[1708]
[1710] Stage a. To a solution of 3-phenylbenzoic 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-aminopipendin-1-carboxylate (0.2 mmol) and DIPEA (0.6 mmol) were added to the reaction mixture at rt. The reaction mixture was stirred at rt for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by prep TLC. (PE / EtOAc = 1: 2) yielding tert-butyl 3- ([1,1'-biphenyl] -3-ylcarboxamido) piperidine-1-carboxylate. MS: ES + 381.4.
[1711] Stages b, c. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1. LCMS: Method D, RT 2.82 min, MS: ES + 306.2.
[1712] Example 2491- (3-benzylphenyl) -3- (1-cyanopiperidin-3-yl) urea
[1714]
[1716] Stage a. To a solution of 1-benzyl-3-isocyanatobenzene (0.2 mmol) in DCM (1 ml) was added tert-butyl 3-aminopiperidine-1-carboxylate (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. The resulting residue was purified by prep TLC. (PE / EtOAc = 1: 2) yielding tert-butyl 3- (3- (3-benzylphenyl) ureido) piperidine-1-carboxylate. MS: ES + 410.5.
[1717] Steps b, C. The title compound was synthesized from the above intermediate using a procedure similar to that described for steps b, c of Example 1, MS: e S + 335.2.
[1718] Example 2501- (1-cyanopiperidin-3-yl) -3- (3-phenoxyphenyl) urea
[1720]
[1722] Synthesized by a procedure similar to that described for Example 249. LCMS: Method D, 2.79 min, MS: ES + 337.2. The compounds in Table 12 were synthesized using a procedure similar to that described for Example 249 using tert-butyl 3-amino-1-pyrrolidinecarboxylate (CAS Number 186550-13-0) in step a.
[1724]
[1726] Table 12
[1728]
[1729]
[1732] Biological activity of the compounds of the invention
[1733] Abbreviations:
[1734] TAMRA carboxytetramethylrhodamine
[1735] PCR polymerase chain reaction
[1736] PBS phosphate buffered saline
[1737] EDTA Ethylenediaminetetraacetic acid
[1738] Tris 2-amino-2- (hydroxymethyl) -1,3-propanediol
[1739] NP-40 Nonidet P-40, octylphenoxypolyethoxyethanol
[1740] BSA bovine serum albumin
[1741] PNS peripheral nervous system
[1742] BH3 Bcl-2 homology domain 3
[1743] PTEN homologous to phosphatase and tensin
[1744] USP30 FP In Vitro Inhibition Assay
[1745] USP30 Biochemical Kinetic Assay. Reactions were run in duplicate on 384-well black plates (small volume, Greiner 784076) in a final reaction volume of 21 gl. USP30 CD (57-517, # 64-0057-050 ubiquigent) was diluted in reaction buffer (40 mM Tris, pH 7.5, 0.005% Tween 20, 0.5 mg / ml BSA, beta-mercaptoethanol 5 mM) to the equivalent of 0, 0.005, 0.01, 0.05, 0.1 and 0.5 gl / well. The buffer was optimized for optimal temperature, pH, reducing agent, salts, incubation time, and detergent. Reactions started by adding 50 nM TAMRA-labeled peptide linked to ubiquitin via an isopeptide bond as a fluorescence polarization substrate. Reactions were incubated at room temperature and read every 2 min for 120 min. Readings were done on a Pherastar Plus (BMG Labtech). At Excitation 540 nm; A Emission 590 nm.
[1747] USP30 IC50 Biochemical Assay
[1749] Dilution plates were prepared at 21 times the final concentration (2100 pM for a final concentration of 100 pM) in 50% DMSO in a 96-well polypropylene V-bottom plate (Greiner # 651201). A typical 8 point dilution series would be 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 pM final. Reactions were run in duplicate on 384-well black plates (small volume, Greiner 784076) in a final reaction volume of 21 µl. 1 µl 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 µl / well and added 10 µl of diluted USP30 to the compound. The enzyme and compound were incubated for 30 min at room temperature. Reactions were initiated by the addition of 50 nM TAMRA-labeled peptide bound to ubiquitin via an isopeptide bond as a fluorescence polarization substrate. Reactions were read immediately after addition of substrate and after a 2 hour incubation at room temperature. Readings were done on a Pherastar Plus (BMG Labtech). At Excitation 540 nm; A Emission 590 nm.
[1750] USP30 FI In Vitro Inhibition Assay
[1752] USP30 Biochemical Fluorescence Intensity Kinetic Assay. Reactions were run in duplicate on 384-well black plates (small volume, Greiner 784076) in a final reaction volume of 21 µl. USP30 CD (Boston Biochem E-582 or 57-517, # 64-0057-050 Ubiquigent) was diluted in reaction buffer (40 mM Tris, pH 7.5, 0.005% Tween 20, 0.5 mg / ml of BSA, 5 mM beta-mercaptoethanol) to the equivalent of 0, 0.0005, 0.001, 0.005 and 0.01 µl / well. The buffer was optimized for optimal temperature, pH, reducing agent, salts, incubation time, and detergent. Reactions were initiated by the addition of ubiquitin-rhodamine 110 (U-555, Boston Biochem) to a final concentration of 100 nM. Reactions were incubated at room temperature and read every 2 min for 120 min. Readings were done on a Pherastar Plus (BMG Labtech). A Excitation 487 nm; A Emission 535 nm.
[1754] USP30 Fluorescence Intensity IC 50 Biochemical Assay
[1756] Dilution plates were prepared at 21 times the final concentration (2100 pM for a final concentration of 100 pM) in 50% DMSO in a 96-well polypropylene V-bottom plate (Greiner # 651201). A typical 8 point dilution series would be 100, 30, 10, 3, 1, 0.3, 0.1.0.03 pM final. Reactions were run in duplicate on 384-well black plates (small volume, Greiner 784076) in a final reaction volume of 21 µl.
[1757] 1 µl 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 0.001 µl / well and 10 pl of USP30 diluted to compound. The enzyme and compound were incubated for 30 min at room temperature. Reactions were initiated by the addition of ubiquitin-rhodamine 110 (U-555; Boston Biochem) to a final concentration of 100 nM. Reactions were read immediately after addition of substrate and after a 2 hr incubation at room temperature. Readings were done on a Pherastar Plus (BMG Labtech). A Excitation 487 nm; A Emission 535 nm.
[1759] Activity of Illustrative Compounds in the USP30 IC50 FP or FI Biochemical Assay
[1761] Ranks
[1763] A <0.1 pM;
[1765] 0.1 <B <1 pM;
[1767] 1pM <C <10pM;
[1769] 10pM <D <30pM
[1770]
[1771]
[1772]
[1773]

权利要求:
Claims (1)
[0001]
1. A compound of formula (II)

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: m is 0 or 1;
when m is 1, Z is -C (R6) (R7) -;
R2 represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
R3, R4 and R5 each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
R1, R6, R7 and R8 each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
R9 represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R10;
R10 represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R9, or forms a monocyclic ring with R11;
Y represents a covalent bond, -C0-C3 alkylene -N (R11) -C0-C3 alkylene or C1-C3 alkylene;
R11 represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R10;
R12 represents a monocyclic, optionally substituted bicyclic, or optionally substituted tricyclic 3- to 14-membered heteroaryl, heterocyclyl or cycloalkyl ring;
where R12, when substituted, is substituted with one or more of -Q1- (R13) p, where:
p is 0 or 1;
Q1 represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C0-C3) -NR14-, -alkylene (C0-C3) -NR14R15, -alkylene (C0-C3) -CONR14-, - alkylene (C0-C3) -NR14CO-, -alkylene (C0-C3) -NR14SO2-, an oxygen atom, -alkylene (C0-C3) -CO-, -alkylene (C0-C3) -S (O) q -,-(C0-C3) -alkylene -SO2NR14, -alkylene (C0-C3) -SO2NR14R15, -C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C0-C3) -SO2R14, -alkylene (C0-C3) -NR14COR15, -alkylene (C0-C3) -NR14CONR15R16, -alkylene (C0-C3) -NR14SO2NR15R16, -alkylene (C0-C3) -CONR14R15, -alkylene (C0-C3) -alkylene (C0-C3) -alkylene (C0-C3) -alkylene (C0-C3) -NR14CO2R15, -alkylene (C0-C3) -SO2NR14R15, -alkylene (C0-C3) -C (O) R14 and alkylene (C1-C6) -NR14SO2R15, NO2, C1-C6 alkylene, -alkenylene C2-C6, or an optionally substituted -C1-C6 alkyl group;
q is 0, 1 or 2;
R14, R15 and R16 each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group;
when p is 1, R13 represents a 4 to 10 membered heteroaryl, heterocyclyl, aryl or 3 to 8 membered cycloalkyl ring; wherein R13 may be optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl , oxo, cyano, -Q2-R17, -Q2-NR17CONR18R19, -Q2-NR17R18, -Q2-COR17, -Q2-NR17COR18, -Q2-NR17CO2R18, -Q2-SO2R17, Q2-CONR17R18, -Q2-CO2R17, - Q2-SO2NR17R18, -Q2-NR17SO2R18, heterocyclyl, cycloalkyl, heteroaryl and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may optionally be substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CHs) 2, and CO2CH2CH3;
Q2 represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group;
R16, R17, R18 each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl; Y
wherein the optional alkyl substituents of R1, R2, R3, R7, R8, R10 and others are selected from C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano, amino, amido, nitro and SF5.
2. A compound according to claim 1, wherein the heteroaryl, heterocyclyl or cycloalkyl ring of R12 is selected from the group consisting of pyrrolidinyl, thiazolyl, pyridinyl, dihydropyridinyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, indolyl, benzimidazolyl, quinolinyl, azetidinyl, indazolyl, pyrazolopyridinyl, imidazopyridinyl, indolinyl, piperazinyl, morpholinyl, diazepanyl, tetrahydro-2H-pyrido [3,4-b] indolyl, benzomorpholinyl, and pyrrolopyridinyl.
3. A compound according to claim 1 or claim 2, wherein the heterocyclyl ring of R12 is a nitrogen-containing ring selected from azetidinyl and pyrrolidinyl, and Y is a covalent bond that is attached to the nitrogen of the azetidinyl or pyrrolidinyl ring .
4. A compound according to any one of claims 1 to 3, wherein the heteroaryl, heterocyclyl, aryl or cycloalkyl ring of R13 is selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, morpholinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl , benzopyrazolyl, isoindolinyl, tetrahydroquinolinyl, homopiperazinyl, pyrimidinyl, imidazopyrimidinyl, imidazopyridinyl, indazolyl, pyrrolopyridinyl, isoxazolyl, benzimidazolyl, pyridazinyl, cyclopropyl, pyrazolopyrimidinyl, pyrrolopyrimidanyl, eyrimidinyl, pyrrolopyrimidanyl.
5. A compound of formula (II)

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:
m is 0 or 1;
when m is 1, Z is -C (R6) (R7) -;
R2 represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
R3, R4 and R5 each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
R1, R6, R7 and R8 each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
R9 represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R10;
R10 represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R9, or forms a monocyclic ring with R11;
Y represents a covalent bond, -C0-C3 alkylene -N (R11) -C0-C3 alkylene or C1-C3 alkylene;
R11 represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R10;
R12 represents a 3- to 14-membered monocyclic substituted, optionally substituted bicyclic or aryl ring
optionally substituted tricyclic;
wherein R12, when substituted, is substituted with one or more of -Q1- (R13) p, wherein:
p is 0 or 1;
Q1 represents a halogen atom, cyano, oxo, hydroxyl, a covalent bond, -alkylene (C0-C3) -NR14-, -alkylene (C0-C3) -NR14R15, -alkylene (C0-C3) -CONR14-, - alkylene (C0-C3) -NR14CO-, -alkylene (C0-C3) -NR14SO2-, an oxygen atom, -alkylene (C0-C3) -CO-, -alkylene (C0-C3) -S (O) q -,-(C0-C3) -alkylene -SO2NR14R15, -C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C0-C3) -SO2R14, -alkylene (C0-C3) -NR14COR15, -alkylene (C0-C3) -NR14CONR15R16, -alkylene (C0-C3) -NR14SO2NR15R16, -alkylene (C0-C3) -CONR14R15, -alkylene (C0-C3) -CO2R14, -alkylene (C0-C3) -NR14R15, -NR14 (C0-C3) -SO2NR14R15, -alkylene (C0-C3) -C (O) R14 and alkylene (CrC6) -NR14SO2R15, NO2, C1-C6 alkylene, -C2-C6 alkenylene, or a -C1-C6 alkyl group optionally substituted;
q is 0, 1 or 2;
R14, R15 and R16 each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group; when p is 1, R13 represents a 4- to 10-membered heteroaryl, heterocyclyl, or 3- to 8-membered cycloalkyl ring; wherein R13 may be optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl , oxo, cyano, -Q2-R17, -Q2-NR17CONR18R19, -Q2-NR17R18, -Q2-COR17, -Q2-NR17COR18, -Q2-NR17CO2R18, -Q2-SO2R17, Q2-CONR17R18, -Q2-CO2R17, - Q2-SO2NR17R18, -Q2-NR17SO2R18, heterocyclyl, cycloalkyl, heteroaryl and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH3 ) 2, and CO2CH2CH3;
Q2 represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; R16, R17, R18 each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl;
wherein the optional alkyl substituents of R1, R2, R3, R4, R5, R6, R7, R8, R10 and Q1, which may be the same or different, are selected from C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano , amino, amido, nitro and SF5; and where the compound does not have the formula:

6. A compound according to claim 5, wherein the aryl ring of R12 is phenyl.
7. A compound according to claim 5 or claim 6, wherein the heteroaryl, heterocyclyl or cycloalkyl ring of R13 is selected from pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, morpholinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl, benzopyrazolyl, isoindolinyl, tetrahydroquinolinyl, homopiperazinyl, pyrimidinyl, imidazopyrimidinyl, imidazopyridinyl, indazolyl, pyrrolopyridinyl, isoxazolyl, benzimidazolyl, pyridazinyl, cyclopropyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, dihydroisopyridinyl, and dihydroisopyridinyl.
8. A compound according to any one of claims 1 to 7, wherein Q1 is selected from halogen, cyano, oxo, a covalent bond, -NR14R15, -NR14CO-, an oxygen atom, C1-C6 alkoxy, -NR14- , -NR14COR15, C1-C6 alkyl, C1-C3 alkylene, wherein the alkyl and alkoxy are optionally substituted with fluorine; and R14 and R15 each independently represent a hydrogen atom or C1-C3 alkyl.
9. A compound of formula (II)

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: m is 0 or 1;
when m is 1, Z is -C (R6) (R7) -;
R2 represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or C1-C6 alkoxy;
R3, R4 and R5 each independently represent a hydrogen atom, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
R1, R6, R7 and R8 each independently represent a hydrogen atom, a fluorine atom, cyano, hydroxyl, an optionally substituted C1-C3 alkyl group, or C1-C3 alkoxy;
R9 represents a hydrogen atom, a fluorine atom, cyano, hydroxyl, C1-C6 alkyl, a C1-C3 alkoxy group, or a 3- to 8-membered cycloalkyl ring, or forms a heterocyclic ring with R10;
R10 represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring with R9, or forms a monocyclic ring with R11;
Y represents a covalent bond, -C0-C3 alkylene -N (R11) -C0-C3 alkylene or C1-C3 alkylene;
R11 represents a hydrogen atom, C1-C6 alkyl, or forms a monocyclic ring with R10;
R12 represents a 3- to 14-membered monocyclic, bicyclic or tricyclic aryl ring;
where R12 is substituted with one or more of -Q1- (R13) p, where:
p is 1;
Q1 represents cyano, oxo, hydroxyl, a covalent bond, -alkylene (C0-C3) -NR14-, -alkylene (C0-C3) -NR14R15, -alkylene (C0-C3) -CONR14-, -alkylene (C0-C3 ) -NR14CO-, -alkylene (C0-C3) -NR14SO2-, an oxygen atom, -alkylene (C0-C3) -CO-, -alkylene (C0-C3) -S (O) q-, -alkylene ( C0-C3) -SO2NR14, -alkylene (C0-C3) -SO2NR14R15, -C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -alkylene (C0-C3) -SO2R14, -alkylene (C0-C3) -NR14COR15, -alkylene (C0-C3) -NR14CONR15R16, -alkylene (C0-C3) -NR14SO2NR15R16, -alkylene (C0-C3) -CONR14R15, -alkylene (C0-C3) -CO2R14, -C0-C3) -NR14CO2R15, -alkylene (C0-C3) -SO2NR14R15, -alkylene (C0-C3) -C (O) R14 and alkylene (C1-C6) -NR14SO2R15, NO2, C1-C6 alkylene, -C2-C6 alkenylene, or an optionally substituted -C1-C6 alkyl group;
q is 0, 1 or 2;
R14, R15 and R16 each independently represent a hydrogen atom, C1-C6 alkyl, or a C1-C6 alkylene group; when p is 1, R13 represents a 4 to 10 membered aryl ring; wherein R13 is substituted with one or more substituents selected from C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano , -Q2-R17, -Q2-NR17CONR18R19, -Q2-NR17R18, -Q2-COR17, -Q2-NR17COR18, -Q2-NR17CO2R18, -Q2-SO2R17, Q2-CONR17R18, -Q2-CO2R17, -Q2-SO2NR17, -Q2-SO2NR17 -Q2-NR17SO2R18, heterocyclyl, cycloalkyl, heteroaryl and aryl; wherein said heterocyclyl, cycloalkyl, heteroaryl and aryl rings may be optionally substituted with one or more substituents, which may be the same or different, selected from Cl, F, OMe, Me, COCH3, CONH2, NHC (O) CH (CH3 ) 2, and CO2CH2CH3;
Q2 represents a covalent bond, an oxygen atom, -CO- or a C1-C6 alkylene or C2-C6 alkenylene group; R16, R17, R18 each independently represent hydrogen, C1-C6 alkyl, heterocyclyl, heteroaryl, aryl, or cycloalkyl; Y
wherein the optional alkyl substituents of R1, R2, R3, R4, R5, R6, R7, R8, R10 and Q1, which may be the same or different, are selected from C1-C3 alkoxy, halogen, hydroxyl, thiol, cyano , amino, amido, nitro and SF5.
10. A compound according to claim 9, wherein Q1 is selected from cyano, oxo, a covalent bond, -NR14R15, -NR14CO-, an oxygen atom, C1-C6 alkoxy, -NR14-, -NR14COR15, C1- alkyl C6, C1-C3 alkylene, where alkyl and alkoxy are optionally substituted with fluoro; and R14 and R15 each independently represent a hydrogen atom or C1-C3 alkyl.
11. A compound according to any one of claims 1 to 10, wherein m is 0.
12. A compound according to any one of claims 1 to 11, wherein R10 represents a hydrogen atom, optionally substituted C1-C6 alkyl, or forms a heterocyclic ring optionally substituted with R9, or forms an optionally 5- or 6-membered monocyclic ring replaced with R11-13. A compound according to any one of claims 1 to 12, wherein R1, R3, R4, R5 and R6, R7 and R8 if present, each independently represent a hydrogen atom, and wherein R2 represents hydrogen or methyl.
14. A compound according to any of claims 1 to 13, wherein R9 represents hydrogen, fluorine atom, hydroxyl, methyl, methoxy, cyclopropyl or forms a 5-membered heterocyclic ring with R1a
15. A compound according to any one of claims 1 to 14, wherein R10 forms a 5-membered heterocyclic ring with R9
16. A compound according to any one of claims 1 to 15, having the structure of formula (III)

a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein m, Z, R1, R2, R3, R4, R5, R8, R9, R10, R12 and Y are defined in any of claims 1 to 15 for compounds of formula (II).
17. A compound of formula (II) according to claim 1, which is selected from the group consisting of:
(R) -N- (1-cyanopyrrolidin-3-yl) -5-phenylpicolinamide;
6- (benzyl (methyl) amino) -N- (1-cyanopyrrolidin-3-yl) nicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-phenylazetidine-1-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -4-phenylthiazole-2-carboxamide;
3- (3-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) isoxazole-5-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -1-phenyl-1 H-imidazole-4-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -1- (2,4-difluorobenzyl) -5-oxopyrrolidine-3-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -5-oxo-1-phenylpyrrolidine-3-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -2-phenylquinoline-4-carboxamide;
6- (4-carbamoylpiperidin-1-yl) -N- (1-cyanopyrrolidin-3-yl) nicotinamide;
N- (1-cyanopyrrolidin-3-yl) -6- (4- (2,4-difluorophenyl) piperazin-1-yl) nicotinamide;
Ethyl 4- (5 - ((1-cyanopyrrolidin-3-yl) carbamoyl) pyridin-2-yl) piperazin-1-carboxylate;
N- (1-cyanopyrrolidin-3-yl) -6- (2- (pyridin-3-yl) pyrrolidin-1-yl) nicotinam ida;
N- (1-cyanopyrrolidin-3-yl) -6- (4-phenoxypiperidin-1-yl) nicotinamide;
N- (1-cyanopyrrolidin-3-yl) -6- (4- (pyridin-4-yl) piperidin-1-yl) nicotinam ida;
6- (benzyl (methyl) amino) -N- (1-cyanopyrrolidin-3-yl) picolinamide;
N- (1-cyanopyrrolidin-3-yl) -6- (3,4-dihydroisoquinolin-2 (1H) -yl) picolinamide;
N- (1-cyanopyrrolidin-3-yl) -6- (4-phenoxypiperidin-1-yl) picolinamide;
N- (1-cyanopyrrolidin-3-yl) -2- (3,4-dihydroisoquinolin-2 (1H) -yl) isonicotinamide;
2- (4-acetyl-1,4-diazepan-1 -yl) -N- (1-cyanopyrrolidin-3-yl) isonicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6-phenylpicolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4-phenylpicolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-phenylisoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (pyridin-4-yl) isoxazole-3-carboxamide;
(R) -6- (4-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) nicotinamide;
(R) -2- (2-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) thiazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2-carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -3-phenylpyrrolidin-1-carboxamide;
(S) -N- (1-cyanopyrrolidin-3-yl) -6-phenylpicolinamide;
(R) -1 - (1 -cyanopyrrolidin-3-yl) -3- (imidazo [1,2-a] pyridin-2-yl) -1-methylurea;
(3aR, 6aR) -1- (3-phenyl-1H-pyrazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(3aR, 6aR) -1- (3-phenylisoxazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(3aR, 6aR) -1 - (1-phenyl-1H-imidazole-4-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(3aR, 6aR) -1- (3- (4-methoxyphenyl) -1H-pyrazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (3aR, 6aR) -1- (3- (4-methoxyphenyl) isoxazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (3aR, 6aR) -1- (2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (R) -N- (1-cyanopyrrolidin-3-yl) -5-phenylpyrimidine-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (pyridin-4-yl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (pyridin-3-yl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (pyridin-2-yl) isoxazole-5-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -5-phenylpyridazine-3-carboxamide;
N - ((3S, 4R) -1-cyano-4-methylpyrrolidin-3-yl) -2-phenylthiazole-5-carboxamide;
N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -2-phenylthiazole-5-carboxamide;
N - ((3S, 4R) -1-cyano-4-methylpyrrolidin-3-yl) -5-phenylthiazole-2-carboxamide;
N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -5-phenylthiazole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2- (isoindolin-2-yl) isonicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2- (3,4-dihydroisoquinolin-2 (1H) -yl) isonicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [d] imidazole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-6- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [d] imidazole-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-3-phenoxyazetidine-1-carboxamide;
2- (2-chlorophenyl) -N - ((3R, 4R) -1-cyano-4-hydroxypyrrolidin-3-yl) thiazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (4-methoxyphenyl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (pyridin-2-yl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (2-methoxyphenyl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (2-fluorophenyl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6-morpholinonicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (4-methoxyphenyl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1 H-indazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5-phenyl-1H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (pyridin-3-yl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) nicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carboxamide;
(R) -6- (3-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-2-carboxamide;
(R) -6- (4-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (1-methyl-1H-indazol-5-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (1-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (1,3-dimethyl-1H-pyrazol-4-yl) -3-fluoroopicolinamide;
(R) -3-chloro-N- (1-cyanopyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1,3-dimethyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-indazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -1 H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (1,3-dimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (1-ethyl-1H-pyrazol-4-yl) -4-methylpicolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-phenoxyazetidine-1-carboxamide;
(R) -3- (1 H-benzo [d] imidazol-2-yl) -N- (1-cyanopyrrolidin-3-yl) azetidin-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4-phenylpiperazine-1-carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -2-phenylmorpholin-4-carboxamide;
(R) -4- (2-chloro-6-fluorobenzyl) -N- (1-cyanopyrrolidin-3-yl) -1,4-diazepane-1-carboxamide; (R) -4-benzyl-N- (1-cyanopyrrolidin-3-yl) -1,4-diazepane-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1,3,4,9-tetrahydro-2H-pyrido [3,4-b] indole-2-carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -2 - ((2S, 6R) -2,6-dimethylmorpholino) -5-fluoroisonicotinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5-fluoro-2- (isoindolin-2-yl) isonicotinamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -5-methyl-1 - (1-phenylethyl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5-methyl-1 - (pyridin-2-ylmethyl) -1 H-pyrazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1 -isobutyl-6- (1-methyl-1H-pyrazol-4-yl) -1H-indazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -1-isobutyl-1H-indazole-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1- (cyclopropylmethyl) -6- (3,5-dimethylisoxazol-4-yl) -1H-indazole-3-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -N-methyl-1H-benzo [d] imidazole-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-3-carboxamide;
(R) -7- (3-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) imidazo [1,2-a] pyridine-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-7- (2-methylpyridin-4-yl) imidazo [1,2-a] pyridine-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-7- (6-methylpyridin-3-yl) imidazo [1,2-a] pyridine-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -7- (1,3-dimethyl-1H-pyrazol-4-yl) -N-methylimidazo [1,2-a] pyridine-3-carboxamide ; (R) -N- (1-cyanopyrrolidin-3-yl) -7- (2,6-dimethylpyridin-4-yl) -N-methylimidazo [1,2-a] pyridine-3-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -N-ethyl-7- (2-methylpyridin-4-yl) imidazo [1,2-a] pyridine-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -7-morpholinoimidazo [1,2-a] pyridine-3-carboxamide;
(R) -6- (3-cyanophenyl) -N- (1-cyanopyrrolidin-3-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -6- (1,3-dimethyl-1H-pyrazol-4-yl) -3-fluoroimidazo [1,2-a] pyridine-2-carboxamide ; (R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -3-fluoroimidazo1,2-a] pyridine-2-carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide;
N - ((2R, 3R) -1-cyano-2-methylpyrrolidin-3-yl) -5- (4-fluorophenyl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (1,3-dimethyl-1H-pyrazol-4-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -5- (2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (pyrazolo1,5-a] pyrimidin-5-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-5- (imidazo [1,2-a] pyridin-6-yl) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-3-phenylazetidine-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-3-phenylazetidine-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (4-methoxyphenyl) azetidine-1-carboxamide;
(R) -3- (4-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide;
(R) -3- (3-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide;
(3aR, 6aR) -1 - (3-phenylazetidin-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (3aR, 6aR) -5-cyano-N- (5-phenylpyridin-2-yl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-ethyl-3-phenylazetidine-1-carboxamide;
(R) -3- (2-oxo-3- (4-phenylthiazol-2-yl) imidazolidin-1-yl) pyrrolidin-1-carbonitrile;
(R) -3- (2-oxo-3- (4-phenylthiazol-2-yl) tetrahydropyrimidin-1 (2H) -yl) pyrrolidin-1-carbonitrile;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (pyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (4-cyclopropylpyrimidin-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-carboxamide ; (R) -N- (1-cyanopyrrolidin-3-yl) -4- (N-methylisobutyramido) picolinamide;
(R) -N- (1-cyanopyrrolidin-3-yl) - [2,3'-bipyridine] -6'-carboxamide;
(R) -N- (1-cyanopyrroldin-3-yl) - [2,4'-bipyridine] -2'-carboxamide;
(R) -3- (4-chlorophenyl) -N- (1-cyanopyrrolidin-3-yl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (4- (trifluoromethyl) phenyl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (3,4-dimethoxyphenyl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (3-methoxyphenyl) isoxazole-5-carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -1-phenylpyrrolidine-3-carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -3- (pyridin-2-yl) pyrrolidin-1-carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -3- (1-methyl-1H-pyrazol-4-yl) pyrrolidin-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (2-methoxypyridin-4-yl) -N-methylisoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1-methyl-6- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1-methyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide;
(R) -1 - (1 -cyanopyrrolidin-3-yl) -3- (2- (isoindolin-2-yl) pyridin-4-yl) -1-methylurea;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-f luoro-1-methyl-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-indole-2-carboxamide ;
(R) -N- (1-cyanopyrrolidin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a] pyridine-3-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (1-phenyl-1H-pyrazol-3-yl) azetidine-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (1 - (pyrazin-2-yl) -1 H-pyrazol-3-yl) azetidin-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (2-phenylpyrimidin-4-yl) azetidin-1-carboxamide;
(R) -3- (2- (4-chlorophenyl) pyrimidin-4-yl) -N- (1-cyanopyrrolidin-3-yl) azetidine-1-carboxamide;
(R) -3- (benzyloxy) -N- (1-cyanopyrrolidin-3-yl) -3-phenylazetidine-1-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -1 - (4-cyclopropylpyrimidin-2-yl) indoline-5-carboxam ida;
(R) -N- (1-cyanopyrrolidin-3-yl) -1- (4-cyclopropylpyrimidin-2-yl) -N-methylindoline-5-carboxamide;
(3aR, 6aR) -5-cyano-N- (2'-methyl- [3,4'-bipyridin] -6-yl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
1 - (3-phenyl-1H-pyrazole-5-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(3aR, 6aR) -1 - (3-phenoxyazetidin-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(R) -N- (1-cyanopyrrolidin-3-yl) -6- (3,5-dimethylisoxazol-4-yl) -N-methyl-1H-indole-2-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-pyrrolo [2,3-c] pyridin- 2- carboxamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -N-methyl-2-phenylmorpholin-4-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methylindolin-1-carboxamide;
(R) -1 - (1 -cyanopyrrolidin-3-yl) -1-methyl-3- (6- (trifluoromethyl) pyridin-3-yl) urea;
(R) -3- (5-chloropyridin-2-yl) -1 - (1-cyanopyrrolidin-3-yl) -1-methylurea;
(3aR, 6aR) -1 - (indolin-1-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (3,4-dimethylphenyl) isoxazole-5-carboxamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3- (2,4-difluorophenyl) isoxazole-5-carboxamide; Y
(R) -N- (1-cyanopyrrolidin-3-yl) -N-methyl-3- (2-methylpyridin-4-yl) isoxazole-5-carboxamide;
a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. 18. A compound according to claim 5, which is selected from:
(R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -4 - ((2S, 6R) -2,6-dimethylmorpholino) -3-fluorobenzamide;
N- (1-cyanopyrrolidin-3-yl) -4- (3,5-dimethylisoxazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4-morpholinobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4-morpholinobenzamide;
(R) -4- (3-chloropyridin-4-yl) -N- (1-cyanopyrrolidin-3-yl) benzamide;
(R) -4- (3-chloropyridin-4-yl) -N- (1-cyanopyrrolidin-3-yl) -3-methoxybenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (2-methylpyridin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (2-morpholinopyridin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4-fluoro-3- (pyridin-4-yl) benzam ida;
(R) -N- (1-cyanopyrrolidin-3-yl) -4-fluoro-3- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(S) -N- (1-cyanopyrrolidin-3-yl) -4- (pyridin-4-yl) benzamide;
(R) -4- (3-chloropyridin-4-yl) -N- (1-cyanopyrrolidin-3-yl) -N-methylbenzamide;
(3aR, 6aR) -1- (4-fluoro-3- (pyridin-4-yl) benzoyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
(3aR, 6aR) -1 - (4-fluoro-3- (1-methyl-1H-pyrazol-4-yl) benzoyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (3aR, 6aR) -1- (4- (3-chloropyridin-4-yl) -3-methoxybenzoyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (3aR, 6aR) -1 - (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzoyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile; (R) -N- (1-cyanopyrrolidin-3-yl) -3- (N-methylisobutyramido) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2,5-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (1,3-dimethyl-1H-pyrazol-4-yl) -3-fluorobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (1,3-dimethyl-1H-pyrazol-4-yl) -2-fluorobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (1-ethyl-1H-pyrazol-4-yl) -2-fluorobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (1 - (2-methoxyethyl) -1 H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (5- (trifluoromethyl) -1 H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (1-methyl-1H-indazol-5-yl) benzamide;
(R) -N- (1-cyanopyrroldin-3-yl) -3-fluoro-N-methyl-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(3aR, 6aR) -5-cyano-N- (2-fluoro-4- (trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide; (R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrimidin-2-ylamino) benzamide;
N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -2-fluoro-4 - ((R) -3-methoxypyrrolidin-1-yl) benzamide;
N- (1-cyano-3-methylpyrrolidin-3-yl) -2-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2-methylpyrimidin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrimidin-4-yl) benzamide;
(R) -N- (1-cyanopyrroldin-3-yl) -2-fluoro-4- (imidazo [1,2-a] pyrimidin-6-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamide
(R) -N- (1-cyanopyrrolidin-3-yl) -3,5-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2,6-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (imidazo [1,2-a] pyridin-6-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2-morpholinopyridin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2,3-difluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4- (pyrimidin-2-ylamino) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrrolidin-1-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2,5-difluoro-4-morpholinobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2,5-difluoro-4- (pyrrolidin-1-yl) benzamide;
N - ((R) -1-cyanopyrrolidin-3-yl) -2-fluoro-4 - ((R) -3-methoxypyrrolidin-1-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4- (pyrimidin-2-ylamino) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-methoxy-4 - ((4-methylpyrimidin-2-yl) amino) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4 - ((4-methoxypyrimidin-2-yl) amino) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyridazin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (pyrazolo1,5-a] pyrimidin-5-yl) benzamide;
3-chloro-N - ((3R, 4S) -1-cyano-4-methylpyrrolidin-3-yl) -4-morpholinobenzamide;
N - ((3R, 4R) -1-cyano-4-cyclopropylpyrrolidin-3-yl) -3-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
N - ((3S, 4S) -1-cyano-4-methoxypyrrolidin-3-yl) -N-methyl-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4- (2,6-dimethylpyrimidin-4-yl) -2-fluorobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (5-fluoro-2-methylpyrimidin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2- (trifluoromethyl) pyrimidin-4-yl) benzam ida;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (2-methyl-3H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (imidazo [1,2-a] pyrazin-3-yl) benzamide;
(R) -1 - (1 -cyanopyrrolidin-3-yl) -1-methyl-3- (4- (1-methyl (-1 H-pyrazol-4-yl) phenyl) urea;
(R) -1 - (1 -cyanopyrrolidin-3-yl) -1-methyl-3- (4- (trifluoromethyl) phenyl) urea;
(3aR, 6aR) -N- (4-chloro-2-fluorophenyl) -5-cyanohexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -5-cyano-N- (2-fluoro-4- (trifluoromethoxy) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide; (3aR, 6aR) -5-cyano-N- (4-cyano-2-fluorophenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -5-cyano-N- (4-cyano-2,5-difluorophenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -N- (5-chloro-2-fluorophenyl) -5-cyanohexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -5-cyano-N- (2-fluoro-5- (trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -5-cyano-N- (4- (trifluoromethyl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(R) -1 - (1 -cyanopyrrolidin-3-yl) -1 -ethyl-3- (4- (trifluoromethyl) phenyl) urea;
1 - (1 -cyanopyrrolidin-3-yl) -1 - (2-methoxyethyl) -3- (4- (trifluoromethyl) phenyl) urea;
(R) -N- (1-cyanopyrrolidin-3-yl) -N-ethyl-3-fluoro-4- (1-methyl-1H-pyrazol-4-yl) benzamide;
(R) -3- (3- (3-morpholinophenyl) -2-oxoimidazolidin-1-yl) pyrrolidin-1-carbonitrile;
(R) -N- (1-cyanopyrrolidin-3-yl) -4 - ((4-cyclopropylpyrimidin-2-yl) amino) -3-fluorobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -4 - ((4-cyclopropylpyrimidin-2-yl) amino) -2,3-difluorobenzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-4- (4-methyl-1H-imidazol-1-yl) benzamide;
(R) -N- (1-cyanopyrrolidin-3-yl) -3-fluoro-N-methyl-4- (4-methyl-1H-imidazol-1-yl) benzamide;
(3aR, 6aR) -5-cyano-N- (3- (2-methylpyridin-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -5-cyano-N- (4- (2-methylpyridin-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide;
(3aR, 6aR) -5-cyano-N- (2-fluoro-4- (2-methylpyridin-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxamide; (3aR, 6aR) -5-cyano-N- (2-fluoro-4- (1-methyl-1H-pyrazol-4-yl) phenyl) hexahydropyrrolo [3,4-b] pyrrole-1 (2H) - carboxamide; 1 - (1 -cyanopyrrolidin-3-yl) -3- (2,4-dichlorophenyl) urea;
1 - (1 -cyanopyrrolidin-3-yl) -3- (4- (trifluoromethyl) phenyl) urea;
3- (3-chlorophenyl) -1 - (1-cyanopyrrolidin-3-yl) -1-methylurea;
1 - (1 -cyanopyrrolidin-3-yl) -3- (2,4-dichlorophenyl) -1-methylurea;
1 - (1 -cyanopyrrolidin-3-yl) -1-methyl-3- (4- (trifluoromethyl) phenyl) urea; Y
(3aR, 6aR) -1- (3-chloro-4-morpholinobenzoyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.
19. A compound according to claim 9, which is selected from:
N- (1-cyanopyrrolidin-3-yl) -2'-methoxy- [1,1'-biphenyl] -4-carboxamide;
N- (1-cyanopyrrolidin-3-yl) -4-phenoxybenzamide;
2 - ([1,1'-biphenyl] -4-yl) -N- (1-cyanopyrrolidin-3-yl) acetamide;
(R) -N- (1-cyanopyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide;
(3aR, 6aR) -1 - ([1,1'-biphenyl] -3-carbonyl) hexahydropyrrolo [3,4-b] pyrrole-5 (1H) -carbonitrile;
N- (1-cyanopyrrolidin-3-yl) -N-methyl- [1,1'-biphenyl] -4-carboxamide;
N - ((3R, 4R) -1-cyano-4-fluoropyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide;
N- (1-cyanopiperidin-3-yl) - [1,1'-biphenyl] -3-carboxamide;
1 - (3-benzylphenyl) -3- (1-cyanopiperidin-3-yl) urea;
1 - (1-cyanopiperidin-3-yl) -3- (3-phenoxyphenyl) urea;
1 - (3-benzylphenyl) -3- (1-cyanopyrrolidin-3-yl) urea;
1 - ([1,1'-biphenyl] -4-yl) -3- (1-cyanopyrrolidin-3-yl) urea;
1 - (1-cyanopyrrolidin-3-yl) -3- (3-phenoxyphenyl) urea;
3- (3-benzylphenyl) -) - 1 - (1-cyanopyrrolidin-3-yl) -1-methylurea;
1 - (1-cyanopyrrolidin-3-yl) -1-methyl-3- (3-phenoxyphenyl) urea; Y
3 - ([1,1'-biphenyl] -4-yl) -1 - (1-cyanopyrrolidin-3-yl) -1-methylurea;
a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.
20. A compound selected from:
2'-chloro-N- (1-cyanopyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide;
3'-chloro-N- (1-cyanopyrrolidin-3-yl) - [1,1'-biphenyl] -4-carboxamide; Y
(R) -N- (1-cyanopyrrolidin-3-yl) -2-fluoro-4- (N-methylphenylsulfonamido) benzamide;
a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.
21. A compound according to any one of claims 1 to 20, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, for use as a medicament.
22. A compound according to any one of claims 1 to 20, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, for use in treating a condition involving mitochondrial dysfunction or cancer.
23. A compound for use according to claim 22, wherein the condition involving mitochondrial dysfunction is selected from a neurodegenerative disease; mitochondrial encephalopathy, lactic acidosis, and stroke-like episode syndrome; Leber's hereditary optic neuropathy; Cancer; neuropathy, ataxia, retinitis pigmentosa-Leigh syndrome inherited from the mother; Danon disease; diabetes; metabolic disorders; ischemic heart disease leading to myocardial infarction; psychiatric illnesses, for example schizophrenia; multiple sulfatase deficiency; mucolipidosis II; mucolipidosis III; IV mucolipidosis; gangliosidosis GM1; neuronal ceroid lipofuscinosis; Alpers disease; Barth syndrome; beta-oxidation defects; carnitinaacyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndromes; Coenzyme 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's disease or syndrome; fatal childhood cardiomyopathy; Luft's disease; glutaric aciduria type II; medium chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and irregular red fiber syndrome; mitochondrial cytopathy; recessive mitochondrial ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastrointestinal disorder and encephalopathy; Pearson's syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; short / medium chain 3-hydroxyacyl-CoA dehydrogenase deficiency; and very long chain acyl-CoA dehydrogenase deficiency.
24. A compound for use according to claim 23, wherein the neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, ischemia, cerebrovascular accident, Lewy body dementia and frontotemporal dementia; and Parkinson's disease related to mutations in α-synuclein, parkin, and PINK1, autosomal recessive juvenile Parkinson's disease, in which parkin is mutated.
25. A compound for 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 or other cancers. cancers of tissues, organs, and blood cell cancers such as lymphomas and leukemias, lymphoma, multiple myeloma, colorectal cancer, and non-small cell lung carcinoma; cancer where apoptotic pathways are deregulated; and cancer where the proteins of the BCL-2 family are mutated or over- or under-expressed.
26. A pharmaceutical composition comprising a compound of formula (II) as defined in any one of claims 1 to 20, a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients .

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GBGB1505429.9A|GB201505429D0|2015-03-30|2015-03-30|Novel compounds|

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GBGB1512829.1A|GB201512829D0|2015-07-21|2015-07-21|Novel compounds|

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PCT/GB2016/050851|WO2016156816A1|2015-03-30|2016-03-24|1-cyano-pyrrolidine compounds as usp30 inhibitors|

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