Heterocyclic inhibitors of RIPK1

Abstract

The present specification relates to compounds of formula (I) which are RIPK1 inhibitors, pharmaceutical compositions comprising them and their use as medicaments.

Description

[0001] COMPOUNDS AND THEIR USE

[0002] The present specification claims benefit of priority to European Patent Application No.

[0003] 24222745.2, filed 23 December 2024, the contents of which are hereby incorporated by reference for all purposes.

[0004] Technical Field

[0005] The specification relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them and their use as medicaments.

[0006] Background of the Specification

[0007] Receptor-interacting serine / threonine-protein kinase-1 (RIPK1) is a key mediator of inflammation and cell death (apoptosis / necroptosis). RIPK1 has two distinct functions: (1) scaffolding function which drives NF-KB signaling. This pathway has been extensively studied in the context of TNF Receptor 1 (TNFR1) in response to TNF-a. This pathway regulates cell proliferation, cytokine production, and pro-survival signals (Kelliher, M et. al The death domain kinase RIP mediates the TNF-induced NF-kB signal immunity 1998); (2) The other known function of RIPK1 being its kinase function. Kinase activity is the main driver of RIPK1 mediated cell death and inflammation. Targeting specifically the kinase function was first shown to inhibit inflammation and necroptosis through necrostatins including Nec-1 (Degterev A. et. al Identification of RIPK1 kinase as a specific cellular target of necrostatins Nat. Chem. Biology 2008). RIPK1 function is not only downstream of TNF-a, but other stimuli and initiators of cell death such as toll-like receptors (TLRs), TNF-a death ligand family members (TRAIL / FAS), and viral infections via DNA sensors. Inhibition of chronic inflammation through multiple pathways maybe important to limit tissue damage and hyperactive immune responses.

[0008] Not only has pharmacological inhibition of RIPK1 shown these distinct functions, but also multiple mutant animals have been generated to elucidate these roles. It was initially shown that RIPK1 full protein knock-out resulted in postnatal death in one to three days. It was further demonstrated that this was through inhibition of the NF-kB pathway which as described above, mediates pro-survival signals through proteins such as FLICE-like inhibitory protein (cFLIP), clAPl and A20 (Shan, B., Pan, H., Najafov, A. & Yuan, J. Necroptosis in development and diseases. Genes Dev 2018). In contrast mutant mice which left the scaffolding function intact but inhibited kinase function via RIPK1 knock-in kinase dead mutants, or mutations in the death domain blocking the dimerization-mediated activation have normal survival. Additionally, these mutations rendered the animals resistant to inflammatory diseases (Meng H, et. al Death domain dimerization mediated activation of RIPK1 controls necroptosis and RIPK1 dependent apoptosis (2018); Polykratis A et. al. Cutting Edge: RIPK1 kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo Journal of Immunology 2014); Berger S et. al CuttingEdge: RIPK 1 kinase activity is dispensiable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice Journal of Immunology 2014). With these findings in mind it is critical to inhibit the kinase function without disrupting the scaffolding function.

[0009] RIPK1 has also been genetically linked to multiple disease including, but not limited to inflammatory bowel disease, Psoriasis, Rheumatoid Arthritis, Multiple Sclerosis, Alzheimer Disease, frontotemporal dementia, and amyotrophic lateral sclerosis (reviewed in Mifflin et. al Receptor interacting protein kinase 1 (RIPK1) as a therapeutic target, 2020 nature reviews drug discovery). RIPK1 has been both directly implicated through GWAS studies, but also indirectly through genetics regarding regulators of the RIPK1 pathway in autoimmune and autoinflammatory diseases.

[0010] To date, no inhibitors of RIPK1 have been approved for therapeutic use. Therefore, there remains a need to provide further compounds which are inhibitors of RIPK1.

[0011] Summary of the Specification

[0012] In a first aspect, the present specification provides a compound of formula (I):

[0013]

[0014] wherein:

[0015] R1is C1-4alkyl, C1-4haloalkyl or phenyl; wherein said phenyl may be substituted by one or two R1a;

[0016] each R1ais independently halo, CN, C1-4alkyl or C1-4haloalkyl;

[0017] n is 0, 1 or 2;

[0018] each R2is independently halo or OH;

[0019] m is 1 or 2;

[0020] R10is H, C1-4alkyl or C1-4haloalkyl;

[0021] R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C1-4alkylene(OH); or

[0022] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0023] each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0024] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0025] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;B is a 3-7 membered heterocycloalkyl, 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 8-10 membered bicyclic heteroaryl, each of which may be independently substituted by one or two R30;

[0026] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, C(O)NR30cR30d, NR30eC(O)R30f, S(O)2NR30gR30h, NR30iS(O)2R30j, Ci.4alkylene(CN), C0-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl);

[0027] wherein when R30is Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl), said C3-6cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy or C(O)Ci.4alkyl;

[0028] wherein when B is a 3-7 membered heterocycloalkyl or 8-10 membered bicyclic heteroaryl, each R30may additionally be =0; and

[0029] R30a, R30b, R30c, R30d, R30e, R30f, R30g, R30h, R30iand R30jare each independently H, C1-4alkyl or C1-4haloalkyl; or a pharmaceutically acceptable salt thereof.

[0030] In a further aspect, the specification provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0031] In a further aspect, the specification provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0032] In a further aspect, the specification provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease in which inhibition of RIPK1 provides a therapeutic effect.

[0033] In a further aspect, the specification provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0034] In a further aspect, the specification provides a method of preventing or treating a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.In a further aspect, the specification provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a second active agent.

[0035] In a further aspect, the specification provides a kit comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and instructions for their use in prophylaxis or treatment, such as in the prophylaxis or treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0036] In a further aspect, the specification relates to methods for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, and intermediates useful in the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0037] Brief Description of the Figures

[0038] Figures 1A-F: Show the fold change in micronucleus frequency (indicative of DNA damage), gH2AX foci frequency (indicative of double strand DNA break repair) and the proportion of kinetochore positive micronuclei in assays (indicative of whole chromosome loss) treated with Example 84 (Figures 1A-C) and Example 102 (Figures 1D-F). The shaded areas represented >50% reduction in cell number (cytotoxicity) in A549 (human lung adenocarcinoma) cells.

[0039] Figures 2A-B: Show the change in micronucleated cells (indicative of DNA damage) in an in vitro human TK6 micronucleus assay upon treatment with Example 84 (Figure 2A) and Example 102 (Figure 2B).

[0040] Figures 3A-B: Show the change in MultiFlow assay endpoints upon treatment with Example 84 (Figure 3A) and Example 102 (Figure 3B).

[0041] Figures 4A-B: Show the frequency of micronucleate cells in an in vitro micronucleus assay in mouse L5178Y cells upon treatment with Example 116 in the presence (Figure 4B) and absence (Figure 4A) of a p-Naphthoflavone / Phenobarbital-induced rat liver metabolising system (S-9).

[0042] Detailed Description of the Specification

[0043] Terms not specifically defined herein should be understood to have the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

[0044] The term "alkyl" as used herein includes straight and branched chain saturated groups containing the specified number of carbon atoms. For example, Ci.4alkyl encompasses methyl, ethyl, n-propyl, / so-propyl, n-butyl, / -butyl, t-butyl and s-butyl.The term "haloalkyl" as used herein includes straight chain and branched chain alkyl groups containing the specified number of carbon atoms substituted by one or more halo atoms, such as one or more fluoro atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.

[0045] The term "alkoxy" as used herein includes straight and branched chain alkoxy groups containing the specified number of carbon atoms. Examples of alkoxy groups include methoxy, ethoxy and propoxy (including n-propoxy and iso-propoxy). The term also extends to alkoxy groups in which the oxygen atom is located within the alkyl chain, for example CH2CH2OCH3 or CH2OCH3.

[0046] The term "haloalkoxy" as used herein includes straight and branched chain alkoxy groups containing the specified number of carbon atoms substituted by one or more halo atoms e.g. one or more fluoro atoms. Examples of haloalkoxy groups include methoxy and ethoxy groups substituted with one to three halo atoms, such as one to three fluoro atoms.

[0047] The term "alkylene" as used herein is a bifunctional straight or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms.

[0048] The term "halo" as used herein refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).

[0049] The term "cycloalkyl" as used herein refers to a fully saturated monocyclic, bicyclic, polycyclic, fused or bridged hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl groups include the Cs-ecycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0050] The term "heterocycloalkyl" as used herein refers to a monocyclic, bicyclic, polycyclic, fused or bridged fully saturated ring containing carbon atoms and at least one heteroatom (for example one O, N, P or S; or for example one N and one O; or for example two N) in the ring structure, and having the specified total number of atoms in the ring structure. Examples of heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxathiolidinyl, isoxthiolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, oxanyl, thianyl, morpholinyl, thiomorpholinyl, oxathianyl, dioxanyl, azepanyl, oxepanyl and thiepanyl.

[0051] The term "monocyclic heteroaryl" as used herein refers to a fully aromatic ring containing the specified number of atoms and at least one heteroatom independently selected from N, O or S at each occurrence (such as one or two N). Examples of 5-membered monocyclic heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, furanyl and thiazolyl. Examples of 6-membered monocyclic heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

[0052] The term "bicyclic heteroaryl" as used herein (e.g. 9-10 membered bicyclic heteroaryl) refers to a group comprising two fused rings containing the specific number of atoms, and wherein one or both of the rings contains at least one heteroatom independently selected from N, O or S at each occurrence(such as one, two, three or four N). Bicyclic heteroaryl groups include those wherein both fused rings are aromatic, or wherein one ring is aromatic and the other fused ring is partially or fully unsaturated.

[0053] Examples of bicyclic heteroaryl groups include pyrrolizinyl, indolyl, isoindolyl, indazolyl, indozlizinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 6,7-dihydro-5H-pyrrolo[l,2-a]imidazolyl, 1, 2,3,4-tetrahydropyrrolo[l,2-c]pyrimidinyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, pyrazolo[l,5-a]pyrimidinyl, 1H-benzo[d]imidazolyl, lH-benzo[d][l,2,3]triazolyl, [l,2,4]triazolo[l,5-a]pyridinyl, lH-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, [l,2,4]triazolo[l,5-a]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b] pyridinyl, 2,3-dihydro-lH-benzo[d]imidazolyl, indolinyl and 3H-imidazo[4,5-b]pyridinyl.

[0054] The heterocyclic, monocyclic heteroaryl and bicyclic heteroaryl groups described herein may comprise oxidised N or S atoms (e.g. an N-oxide, S(O) or S(O)2), or these may exist in their neutral form (e.g. N or S). It will be understood that both oxidised and neutral forms of such compounds are encompassed by the present specification.

[0055] In embodiments, a compound of formula (I) is provided. In embodiments, a pharmaceutically acceptable salt of a compound of formula (I) is provided.

[0056] In embodiments, R1is Ci-4alkyl. In embodiments, R1is C1-4haloalkyl. In embodiments, R1is phenyl. In embodiments, the phenyl is substituted by one or two (such as one) R1a. In embodiments, at least one R1ais halo, such as F. In embodiments, at least one R1ais CN. In embodiments, at least one R1ais C1-4alkyl. In embodiments, at least one R1ais C1-4haloalkyl. In embodiments, R1is phenyl substituted by one R1a, and R1ais F or CN. In embodiments, R1is unsubstituted phenyl.

[0057] In embodiments, the carbon bearing R1has the following stereochemistry:

[0058] R1

[0059]

[0060] In embodiments, the carbon bearing R1has the following stereochemistry:

[0061] R1

[0062]

[0063] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, each R2is independently halo (such as F). In embodiments, each R2is independently OH.In embodiments, m is 1. In embodiments, m is 2.

[0064] In embodiments, R10is H. In embodiments, R10is Ci-4alkyl, such as methyl. In embodiments, R10is Ci-4haloalkyl. In embodiments, R10is H or C1-4alkyl (such as methyl).

[0065] In embodiments, R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C1-4alkylene(OH). In embodiments, R11is H. In embodiments, R11is C1-4alkyl, such as methyl. In embodiments, R11is C1-4haloalkyl. In embodiments, R11is C1-4alkoxy, such as CH2OMe. In embodiments, R11is Ci.4haloalkoxy. in embodiments, R11is Ci.4alkylene(OH). In embodiments, R12is H. In embodiments, R12is Ci-4alkyl, such as methyl. In embodiments, R12is Ci.4haloalkyl. In embodiments, R12is Ci.4alkoxy. In embodiments, R12is Ci.4haloalkoxy. In embodiments, R12is Ci.4alkylene(OH).

[0066] In embodiments, R11and R12are each H. In embodiments, R11and R12are each Ci.4alkyl (such as methyl). In embodiments, R11is C1-4alkoxy (such as CH2OMe) and R12is H.

[0067] In embodiments, R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7 membered heterocycloalkyl. In embodiments, R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl, such as cyclohexyl, cyclobutyl or cyclopropyl, for example cyclopropyl. In embodiments, R11and R12together with the carbon atom to which they are attached, form a 3-7 membered heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In embodiments, R11and R12together with the carbon atom to which they are attached, form an oxetanyl, such as a 3-oxetanyl.

[0068] In embodiments, R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7 membered heterocycloalkyl which are each independently substituted by one or two (such as one) R13. In embodiments, at least one R13is halo, such as F. In embodiments, at least one R13is Ci-4alkyl, such as methyl. In embodiments, at least one R13is Ci.4haloalkyl. In embodiments, at least one R13is Ci.4alkoxy, such as OMe. In embodiments, at least one R13is Ci.4haloalkoxy.

[0069] In embodiments, R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7 membered heterocycloalkyl which is:(such as

[0070]

[0071] wherein denotes the point of attachment to N(R10), and denotes the point of attachment to A.

[0072] In embodiments, R11and R12together with the carbon atom to which they are attached, form a C3-

[0073] scycloalkyl or 3-7 membered heterocycloalkyl which

[0074]

[0075] is

[0076] In embodiments, R11and R12together with the carbon atom to which they are attached, form a Ca¬

[0077] scycloalkyl or 3-7 membered heterocycloalkyl which

[0078]

[0079] is

[0080] In embodiments, A is -C≡C-. In embodiments, A is phenyl. In embodiments, A is a 5-6 membered monocyclic heteroaryl. In embodiments, A is a 5-membered monocyclic heteroaryl, such as pyrazolyl or triazolyl. In embodiments, A is a 6-membered monocyclic heteroaryl, such as pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. In embodiments, the phenyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one or two (such as one) R20. In embodiments, at least one R20is CN. In embodiments, at least one R20is halo, such as Cl or F. In embodiments, at least one R20is Ci-4alkyl, such as methyl or ethyl. In embodiments, at least one R20is Ci.4haloalkyl, such as CF3. In embodiments, at least one R20is Ci.4alkoxy, such as OMe. In embodiments, at least one R20is Ci.4haloalkoxy, such as OCF3 or OCHF2. In embodiments, the phenyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one or two (such as one) R20, and each R20is independently CN, Cl, F, methyl, ethyl, CF3, OCF3or OCHF2.In embodiments, A is phenyl or 5-6 membered monocyclic heteroaryl (such as pyridyl, pyrimidinyl or pyridazinyl, for example pyridyl), each of which are independently substituted by one R20, and R20is CN, Cl, F, methyl, ethyl, CF3, OCF3or OCHF2.

[0081] In embodiments, the phenyl and 5-6 monocyclic heteroaryl are each independently unsubstituted.

[0082] In embodiments, A is:

[0083] Me F

[0084] such as:

[0085]

[0086] wherein denotes the point of attachment to C(R11)(R12), and '■ denotes the point of attachment to B.Me

[0087]

[0088] In embodiments, A is

[0089] In embodiments, B is a 3-7 membered heterocycloalkyl, such as a 6-membered heterocycloalkyl, for example morpholinyl or piperazinyl.

[0090] In embodiments, B is a 5-membered monocyclic heteroaryl, such as pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl or thiadiazolyl, for example pyrazolyl. In embodiments, B is phenyl. In embodiments, B is pyridyl. In embodiments, B is pyridazinyl. In embodiments, B is pyrimidinyl. In embodiments, B is pyrazinyl. In embodiments, B is an 8-10 membered bicyclic heteroaryl.

[0091] In embodiments, B is substituted by one or two (such as one) R30. In embodiments, at least one R30is CN. In embodiments, at least one R30is halo, such as F. In embodiments, at least one R30is Ci-4alkyl, such as methyl. In embodiments, at least one R30is Ci.4haloalkyl, such as CHF2. In embodiments, at least one R30is Ci.4alkoxy, such as OMe. In embodiments, at least one R30is Ci.4haloalkoxy, such as OCHF2. In embodiments, at least one R30is NR30aR30b, such as NH2, NHMe or NHEt. In embodiments, at least one R30is C(O)NR30cR30d, such as C(O)NH2. In embodiments, at least one R30is NR30eC(O)R30f. In embodiments, at least one R30is S(O)2NR30gR30h, such as S(O)2NH2. In embodiments, at least one R30is NR30iS(O)2R30j. In embodiments, at least one R30is Ci.4alkylene(CN), such as CH2CN or CH2CH2CN. In embodiments, at least one R30is Co-4alkylene(C3-6cycloalkyl). In embodiments, at least one R30is Co-4alkylene(3-7 membered heterocycloalkyl), such as 3-7 membered heterocycloalkyl, for example oxetanyl, thietanyl 1,1-dioxide or piperidinyl. In embodiments, at least one R30is Co-4alkylene(5-6 membered monocyclic heteroaryl).In embodiments, B is a 3-7 membered heterocycloalkyl or 8-10 membered bicyclic heteroaryl, and at least one R30is =0.

[0092] In embodiments, when at least one R30is Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl), said Cs-ecycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one Ci-4alkyl (such as methyl), Ci.4haloalkyl, C1-4alkoxy (such as CH2CH2OMe), Ci.4haloalkoxy or C(O)Ci.

[0093] 4alkyl (such as C(O)Me). In embodiments, when at least one R30is Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl), said C3-scycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl are each independently unsubstituted.

[0094] In embodiments:

[0095] B is a 5-membered monocyclic heteroaryl (such as pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl or thiad iazolyl, for example pyrazolyl) substituted by one or two R30;

[0096] each R30is independently CN, halo (such as F), Ci.4alkyl (such as methyl), Ci-4haloalkyl (such as CHF2), Ci.4alkoxy (such as OMe), NR30aR30b(such as NH2), Ci-4alkylene(CN) (such as CH2CN or CH2CH2CN) or Co-4alkylene(3-7 membered heterocycloalkyl) (such as oxetanyl or piperidinyl); and

[0097] said 3-7 membered heterocycloalkyl may be substituted by one Ci-4alkyl (such as methyl) or C(O)Ci.4alkyl (such as C(O)Me).

[0098] In embodiments, B is:

[0099]

[0100] OOO65-PCTO1-NP

[0101]

[0102] In embodiments,

[0103] In embodiments,

[0104]

[0105] In embodiments,

[0106]

[0107] In embodiments, B

[0108]

[0109] is

[0110] In embodiments, B

[0111]

[0112] is

[0113] In embodiments,

[0114]

[0115] B is

[0116] In embodiments:

[0117] B is pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl (such as pyrimidinyl) substituted by one or two R30; andeach R30is independently CN, halo (such as F), Ci.4alkyl (such as methyl), Ci-4haloalkyl (such as CHF2), Ci.4alkoxy (such as OMe), NR30aR30b(such as NH2) or C(O)NR30cR30d(such as C(O)NH2).

[0118] In embodiments, B is:

[0119]

[0120] In embodiments,

[0121] In embodiments,

[0122]

[0123] B is0Me

[0124] In embodiments,

[0125]

[0126] In embodiments, B is:

[0127]

[0128] In embodiments, B is:

[0129]

[0130] In embodiments, B is unsubstituted.

[0131] In embodiments, there is provided a compound of formula (IA):

[0132]

[0133] wherein:

[0134] R1is Ci-4alkyl or phenyl; wherein said phenyl may be substituted by one or two Rla;

[0135] each Rlais independently halo or CN;

[0136] n is 0, 1 or 2;

[0137] each R2is independently halo or OH;

[0138] m is 1 or 2;

[0139] R10is H or Ci-4alkyl;

[0140] R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; or

[0141] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0142] each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0143] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0144] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0145] B is a 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one or two R30;

[0146] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, C(O)NR30cR30d, S(O)2NR30gR30h, Ci.4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl);

[0147] wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci-4haloalkoxy or C(O)Ci-4alkyl; and

[0148] R30a, R30b, R30c, R30d, R30gand R30hare each independently H, Ci-4alkyl or Ci.4haloalkyl;

[0149] or a pharmaceutically acceptable salt thereof.

[0150] In embodiments, the compound of formula (IA) or pharmaceutically acceptable salt thereof is a compound of formula (IA-1):

[0151]

[0152] or a pharmaceutically acceptable salt thereof.

[0153] In embodiments, there is provided a compound of formula (IB):R1°

[0154] N

[0155]

[0156] (IB),

[0157] wherein:

[0158] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0159] each Rlais independently halo or CN;

[0160] n is 0, 1 or 2;

[0161] each R2is independently halo or OH;

[0162] m is 1;

[0163] R10is H or Ci-4alkyl;

[0164] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0165] each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0166] A is phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0167] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0168] B is a 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one or two R30;

[0169] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, C(O)NR30cR30d, S(O)2NR30gR30h, Ci.4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl);

[0170] wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci-4haloalkoxy or C(O)Ci-4alkyl; and

[0171] R30a, R30b, R30c, R30d, R30gand R30hare each independently H, Ci-4alkyl or Ci.4haloalkyl;

[0172] or a pharmaceutically acceptable salt thereof.

[0173] In embodiments, the compound of formula (IB) or pharmaceutically acceptable salt thereof is a compound of formula (IB-1):

[0174]

[0175] or a pharmaceutically acceptable salt thereof.

[0176] In embodiments, there is provided a compound of formula (IC):

[0177]

[0178] wherein:

[0179] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0180] each Rlais independently halo or CN;

[0181] R10is H or Ci-4alkyl;

[0182] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0183] each R13is independently halo or Ci-4alkyl;

[0184] A is phenyl or 6 membered monocyclic heteroaryl; wherein said phenyl or 6 membered monocyclic heteroaryl may each be independently substituted by one R20;

[0185] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0186] B is pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl, thiadiazolyl or pyrimidinyl, each of which may be independently substituted by one or two R30;

[0187] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, Ci-4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl);

[0188] wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci-4haloalkoxy or C(O)Ci-4alkyl; and

[0189] R30aand R30bare each independently H, Ci-4alkyl or Ci.4haloalkyl;

[0190] or a pharmaceutically acceptable salt thereof.In embodiments, the compound of formula (IC) or pharmaceutically acceptable salt thereof is a compound of formula (IC-1):

[0191]

[0192] or a pharmaceutically acceptable salt thereof.

[0193] In embodiments, there is provided a compound of formula (ID):

[0194]

[0195] wherein:

[0196] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0197] each Rlais independently halo or CN;

[0198] n is 0, 1 or 2;

[0199] each R2is independently halo or OH;

[0200] m is 1 or 2;

[0201] R10is H or Ci-4alkyl;

[0202] R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; or R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which is

[0203]

[0204] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0205] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; and

[0206]

[0207] or a pharmaceutically acceptable salt thereof.In embodiments, the compound of formula (ID) or pharmaceutically acceptable salt thereof is a compound of formula (ID-1):

[0208]

[0209] or a pharmaceutically acceptable salt thereof.

[0210] In embodiments, there is provided a compound of formula (IE):

[0211]

[0212] (IE),

[0213] wherein:

[0214] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0215] each Rlais independently halo or CN;

[0216] n is 0, 1 or 2;

[0217] each R2is independently halo or OH;

[0218] m is 1 or 2;

[0219] R10is H or Ci-4alkyl;

[0220] R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; or R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which is

[0221]

[0222] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0223] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; and

[0224]

[0225] or a pharmaceutically acceptable salt thereof.

[0226] In embodiments, the compound of formula (IE) or pharmaceutically acceptable salt thereof is a compound of formula (IE-1):

[0227]

[0228] or a pharmaceutically acceptable salt thereof.

[0229] In embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein:

[0230] B is pyrimidinyl which may be substituted by one or two R30;

[0231] each R30is independently CN, Ci-4alkyl, Ci.4alkoxy or NR30aR30b;

[0232] R30aand R30bare each independently H or Ci-4alkyl;

[0233] A is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one or two R20;

[0234] each R20is halo or Ci-4alkyl;

[0235] R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3- 7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13; and

[0236] each R13is halo,

[0237] wherein R1, R2, n, m and R10are as defined herein.

[0238] In embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein:

[0239] B is pyrazolyl which may be substituted by or two R30;

[0240] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl); wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be substituted by one Ci-4alkyl, Ci.4alkoxy or C(O)Ci-4alkyl;

[0241] A is phenyl, pyridyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one R20;

[0242] R20is Ci-4alkyl;R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3- 7 membered heterocycloalkyl, each of which may be independently substituted by one R13; and each R13is Ci-4alkyl,

[0243] wherein R1, R2, n, m and R10are as defined herein.

[0244] In embodiments, there is provided a compound or pharmaceutically acceptable salt thereof which is:

[0245] (5S)- / V-{3-[4-(6-cyanopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0246] (5S)- / V-{3-[4-(6-aminopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0247] (5S)- / V-{3-[4-(5-aminopyrazin-2-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0248] (5S)- / V-(3-{4-[2-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0249] (5S)-N-{3-[4-(6-amino-5-methylpyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0250] (5S)-N-(3-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0251] (5S)-N-{3-[4-(2-fluoropyridin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0252] (5S)-N-{3-[4-(2-amino-4-methylpyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0253] (5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyridin-8-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0254] (5S)-N-[3-(4'-carbamoyl-3'-fluoro[l,l'-biphenyl]-4-yl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0255] (5S)-N-{3-[4-(2-oxo-2,3-dihydro-lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0256] (5S)-5-phenyl-N-{3-[4-(lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0257] (5S)-N-{3-[4-(2-aminopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0258] (5S)-5-phenyl-N-[3-(4'-sulfamoyl[l,l'-biphenyl]-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-oxo-2,3-dihydro-1H-indol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0259] (5S)-N-{3-[4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0260] (5S)-N-{3-[4-(3-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0261] (5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0262] (5S)-N-{3-[4-(2-methoxypyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0263] (5S)-N-(3-{4-[l-(cyanomethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0264] (5S)-N-(3-{4-[(3R)-3-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0265] (5S)-5-phenyl-N-{3-[4-(pyrimidin-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0266] (5S)-5-phenyl-N-{3-[4-(pyridin-3-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0267] (5S)-N-(3-{4-[6-(difluoromethyl)pyridin-3-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0268] (5S)-N-{3-[4-(5-methylpyridazin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0269] (5S)-N-(3-{4-[(3S)-3-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0270] (5S)-N-(3-{4-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0271] (5S)-N-{3-[4-(2-methoxypyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0272] (5S)-N-(3-{4-[l-(l-acetylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0273] (5S)-N-{3-[4-(6-fluoropyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0274] (5S)-N-(3-{4-[l-(oxetan-3-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0275] (5S)-N-{3-[4-(2-methyl-l,3-thiazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(l-acetylpiperidin-4-yl)-5-methyl-lH-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0276] (5S)-5-phenyl-N-{3-[4-(l,3-thiazol-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0277] (5S)-N-{3-[4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0278] (5S)-N-(3-{4-[l-(2-cyanoethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0279] (5S)-N-{3-[4-(5-fluoro-l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0280] (5S)-N-(3-{4-[l-(l,l-dioxo-lX6-thietan-3-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0281] (5S)-N-{3-[4-(3-cyanopyrazolo[l,5-a]pyrimidin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0282] (5S)-5-phenyl-N-{3-[4-(lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0283] (5S)- / V-{3-[4-(l-methyl-lH-irnidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0284] (5S)-N-{3-[4-(lH-benzotriazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0285] (5S)-N-{3-[4-(l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0286] (5S)-N-{3-[4-(l,3-dimethyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0287] (5S)-N-{3-[4-(lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0288] (5S)-N-{3-[4-(l,2-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0289] (5S)-N-{3-[4-(3-methoxy-l-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0290] (5S)-N-{3-[4-(2-amino-4-methoxypyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0291] (5S)-N-{3-[4-(2-amino-lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0292] (5S)- / V-{3-[4-(5-amino-lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-aminopyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0293] (5S)-N-{3-[4-(6-aminopyridazin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0294] (5S)-N-{3-[4-(2-amino[l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0295] (5S)-N-{3-[4-(l,4-dimethyl-lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0296] (5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyrimidin-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0297] (5S)-N-{3-[4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0298] (5S)-N-{3-[4-(lH-imidazo[4,5-b]pyridin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0299] (5S)-N-{3-[4-(5-cyano-l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0300] (5S)-N-{3-[4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0301] (5S)-N-{3-[4-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0302] (5S)-N-{3-[4-(6-amino-5-methylpyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0303] (5S)-N-{3-[4-(2-amino-4-ethylpyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0304] (5S)-N-{3-[4-(2,4-diaminopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0305] (5S)-N-(3-{4-[2-amino-4-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0306] (5S)-N-{3-[4-(5-methyl-l,3-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0307] (5S)-N-(3-{4-[2-(ethylamino)-4-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0308] (5S)-N-{3-[4-(2-amino-5-methyl-l,3-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0309] (5S)- / V-{3-[4-(3H-imidazo[4,5-b]pyridin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(4-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0310] (5S)-N-{3-[4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0311] (5S)-5-phenyl- / V-{3-[4-(l,3,4-thiadiazol-2-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0312] (5S)- / V-{3-[4-(6-aminopyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0313] (5S)- / V-{3-[4-(2-amino-4-cyanopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0314] (5S)- / V-(3-{4-[(3RS)-3-carbamoylpiperidin-l-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0315] (5S)-N-{3-[4-(3-oxopiperazin-l-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0316] (5S)-N-{3-[4-(morpholin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole- 2-carboxamide;

[0317] (5S)- / V-(3-{4-[5-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0318] (5S)-N-{3-[4-(5-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0319] (5S)- / V-{3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0320] (5S)-N-{3-[4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0321] (5S)- / V-{3-[4-(4-amino-l-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0322] (5S)-N-[3-(4-{1-[1-(2-methoxyethyl)piperidin-4-yl]-1H-pyrazol-4-yl}phenyl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0323] (5S)- / V-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0324] (5S)- / V-{3-[6-(2-aminopyrimidin-5-yl)pyridazin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0325] (5S)-N-{3-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0326] (5S)-N-{1-[6-(6-amino-4-methylpyridin-3-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-amino-4-methoxypyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0327] (5S)-N-{1-[6-(6-amino-4-methoxypyridin-3-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0328] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0329] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0330] (5S)-N-{1-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0331] (5S)-N-{1-[5-(3-methyl-1H-pyrazol-4-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0332] (5S)-N-{1-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0333] (5S)-N-{1-[6-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0334] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0335] (5S)-N-[l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0336] (5S)-N-[l-(2'-amino-4'-methyl[5,5'-bipyrimidin]-2-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0337] (5S)-N-[l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0338] (5S)-N-{1-[4-(2-aminopyrimidin-5-yl)-3-methylphenyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0339] (5S)-N-{1-[4-(2-aminopyrimidin-5-yl)-2-methylphenyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0340] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0341] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0342] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0343] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0344] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0345] (5S)-N-(l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0346] (5S)-N-[l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0347] (5S)-N-(l-{5-methyl-6-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0348] (5S)-N-(l-{6-[l-(difluoromethyl)-lH-l7273-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-677-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0349] (5S)-N-(1-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0350] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0351] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0352] (5S)- / V-(l-{5-methyl-6-[l-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0353] (5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0354] (5S)-N-(3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0355] (5S)-N-{3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0356] (5S)-N-{3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0357] (5S)-N-{3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0358] (5S)- / V-{3-[5-methyl-6-(5-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0359] (5S)- / V-(3-{6-[l-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0360] (5S)- / V-(3-{6-[l-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0361] 1(5S)-N-(3-{5-methyl-6-[1-(2H3)methyl-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0362] (5S)-N-({6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}methyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0363] (5S)-N-[{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0364] (5S)-N-[(lR)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0365] (5S)-N-[(lS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0366] (5S)-N-(2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0367] (5S)-N-[(lR,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0368] (5S)-N-[(lS,2R)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0369] (5S)-N-(l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutyl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0370] (5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0371] (5S)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0372] (5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0373] (5S)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0374] (5S)-5-(3-cyanophenyl)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0375] (5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0376] (5S)- / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0377] (5S)- / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0378] (5R)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5R)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0379] (5S)- / V-(3-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylphenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0380] (5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0381] (5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methyl-l-oxo-lX5-pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0382] (5S)-N-{1-[1-(2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazol-4-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0383] (5S)-N-(3-{1-[2-(difluoromethyl)-2H-indazol-5-yl]-1H-pyrazol-4-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0384] (5S)- / V-{3-[l-(2-amino[l,2,4]triazolo[l,5-a]pyridin-7-yl)-1H-pyrazol-4-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0385] (5S)-N-(3-{1-[2-(difluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]-1H-pyrazol-4-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0386] (5S)-N-(1-{1-[4-(difluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0387] (5S)- / V-(l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0388] (5S)- / V-(3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0389] (5S)-N-{1-[(2-aminopyrimidin-5-yl)ethynyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0390] (5S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0391] (5S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-5-(3-cyanophenyl)-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0392] (5S)-5-(3-cyanophenyl)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0393] (5S)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0394] (5S)- / V-[(lR)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0395] (5S)- / V-[(lS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-[(lR)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0396] (5S)- / V-[(lS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0397] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0398] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclohexyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0399] (5S)-N-(4-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxan-4-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0400] (5S)-N-{(lS)-l-[4-(2-aminopyrimidin-5-yl)phenyl]propyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0401] (5S)-N-{(3R)-3-[4-(2-aminopyrimidin-5-yl)phenyl]oxolan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0402] (5S)-N-{(3S)-3-[4-(2-aminopyrimidin-5-yl)phenyl]oxolan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0403] (5S)-N-[(lR)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methoxyethyl]-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0404] (5S)-N-[(lS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methoxyethyl]-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0405] (5S)-N-{1-[4-(2-aminopyrimidin-5-yl)phenyl]-3,3-difluorocyclobutyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0406] (5S,7S)- / V-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0407] (5S,7S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0408] (5S,7S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0409] (5S,7S)-N-{1-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0410] (5S,7S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0411] (5S,7R)-N-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0412] (5S)-N-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{3-chloro-4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0413] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methoxypyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0414] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methoxyphenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0415] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3,5-difluorophenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0416] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0417] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluoropyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0418] (5S)-N-(l-{3-cyano-4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0419] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0420] (5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethoxy)phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0421] (5S)-N-(1-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylpyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0422] (5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3,5-dimethylphenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0423] (5R)-N-(1-{3-(difluoromethoxy)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0424] (5S)-N-(1-{3-(difluoromethoxy)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0425] (5S)-N-(1-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0426] (5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluoro-3-methoxyphenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; or

[0427] (5S)-N-(1-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyrimidin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide,

[0428] or a pharmaceutically acceptable salt of any one thereof.

[0429] It will be understood that references to compounds of formula (I) and pharmaceutically acceptable salts thereof throughout this specification apply equally to other compounds andpharmaceutically acceptable salts described herein, such as compounds of formulae (IA), (IA-1), (IB), (IB-I), (IC), (IC-I), (ID), (ID-1) (IE) or (IE-1) and pharmaceutically acceptable salts of any one thereof.

[0430] The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include13C and14C. Isotopically labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically labelled reagents in place of the non-labelled reagents previously employed.

[0431] A suitable pharmaceutically acceptable salt of a compound of the formula (I) may be, for example, an acid addition salt or a base addition salt. A suitable pharmaceutically acceptable salt of a compound of the formula (I) may be, for example, an acid-addition salt of a compound of the formula (I), for example an acid-addition salt with an inorganic or organic acid. The compounds of the specification may be provided as the free compound, i.e. in the non-salified state. Certain of the compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base. The present specification is intended to include all possible stoichiometric and non-stoichiometric forms of acid- and base-addition salts. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.

[0432] A further suitable pharmaceutically acceptable salt of a compound of formula (I) may be, for example, a salt formed within the human or animal body after administration of a compound of formula (I) to said human or animal body.

[0433] The compounds of formula (I) or pharmaceutically acceptable salts thereof may be solvated. The present specification is intended to include all stoichiometric and non-stoichiometric solvates. It will be understood that the present specification encompasses pharmaceutically acceptable prodrugs of compounds of formula (I) and their pharmaceutically acceptable salts i.e. pharmaceutically acceptable derivatives which, upon administration to a subject, are capable of directly or indirectly providing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Further information on pharmaceutically acceptable prodrugs can be found, for example, in Rautio, J., Meanwell, N., Di, L. et al., Nat Rev Drug Discov 17, 559-587 (2018).It will be understood that the present specification encompasses all isomers of compounds of formula (I) and their pharmaceutically acceptable salts, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I) and their pharmaceutically acceptable salts, the present specification includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0434] Therapeutic Uses

[0435] The compounds and pharmaceutically acceptable salts of the specification are inhibitors of RIPK1. Therefore, the compounds and pharmaceutically acceptable salts of the specification are expected to be useful in the prophylaxis or treatment of diseases in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0436] As used herein, "prophylaxis" is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease or condition and secondary prophylaxis whereby the disease or condition has already developed and the subject is temporarily or permanently protected against exacerbation or worsening of the disease or condition, or the development of new symptoms associated with the disease or condition. The terms "prophylactic", "preventing" and "prevention" are used synonymously with "prophylaxis".

[0437] As used herein, "treatment" is intended to have its normal meaning of dealing with a disease or condition in order to entirely or partially relieve one, some or all of its symptoms in a subject, or to correct or compensate for the underlying pathology. The terms "treatment" and "treating" are used synonymously with "therapy".

[0438] In embodiments, the specification provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0439] In embodiments, the specification provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0440] In embodiments, the specification provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prophylaxis of a disease in which inhibition of RIPK1 provides a prophylactic effect.In embodiments, the specification provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease in which inhibition of RIPK1 provides a therapeutic effect.

[0441] In embodiments, the specification provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0442] In embodiments, the specification provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis of a disease in which inhibition of RIPK1 provides a prophylactic effect.

[0443] In embodiments, the specification provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease in which inhibition of RIPK1 provides a therapeutic effect.

[0444] In embodiments, the specification provides a method of preventing or treating a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0445] In embodiments, the specification provides a method of preventing a disease in which inhibition of RIPK1 provides a prophylactic effect, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0446] In embodiments, the specification provides a method of treating a disease in which inhibition of RIPK1 provides a therapeutic effect, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0447] In embodiments, the disease is an inflammatory disease.

[0448] In embodiments, the inflammatory disease is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune lymphoproliferative syndrome (APS), arthritis (such as osteoarthritis), rheumatoid arthritis (RA), non-communicable inflammatory skin diseases (ncISD) (such as psoriasis (PsO) or atopic dermatitis (AD)), asthma, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), systemic sclerosis (SSc), chronic obstructive pulmonary disease (COPD), lysosomal storage disorders, sepsis, acute kidney disease (AKD), chronic kidney disease (CKD), Sjogren's syndrome (SjS), celiac disease, atherosclerosis, Crohn's disease (CD), colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematous (SLE), lupus or other forms of nephritis, Parkinson's disease or ulcerative colitis (UC).In embodiments, the inflammatory disease is an inflammatory disease of the intestines, such as Crohn's disease or ulcerative colitis.

[0449] In embodiments, the subject is a mammal, such as a human.

[0450] Pharmaceutical Compositions

[0451] The term "pharmaceutical composition", as used herein, refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be expressed, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. Such compositions can be sterile.

[0452] For use in prophylaxis or therapy, a compound of formula (I) or a pharmaceutically acceptable salt thereof will typically be administered in the form of a pharmaceutical composition.

[0453] Therefore, in embodiments the specification provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0454] In embodiments, the specification provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use as a medicament.

[0455] In embodiments, the specification provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use in the prophylaxis or treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect, such as the diseases disclosed herein.

[0456] In embodiments, the specification provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use in the prophylaxis of a disease in which inhibition of RIPK1 provides a prophylactic effect, such as the diseases disclosed herein.

[0457] In embodiments, the specification provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use in the treatment of a disease in which inhibition of RIPK1 provides a therapeutic effect, such as the diseases disclosed herein.In embodiments, the specification provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the prophylaxis or treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect, such as the diseases disclosed herein.

[0458] In embodiments, the specification provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the prophylaxis of a disease in which inhibition of RIPK1 provides a prophylactic effect, such as the diseases disclosed herein.

[0459] In embodiments, the specification provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disease in which inhibition of RIPK1 provides a therapeutic effect, such as the diseases disclosed herein.

[0460] In embodiments, the specification provides a method of preventing or treating a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect, such as the diseases disclosed herein, comprising administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0461] In embodiments, the specification provides a method of preventing a disease in which inhibition of RIPK1 provides a prophylactic effect, such as the diseases disclosed herein, comprising administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0462] In embodiments, the specification provides a method of treating a disease in which inhibition of RIPK1 provides a therapeutic effect, such as the diseases disclosed herein, comprising administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0463] Pharmaceutical compositions according to the present specification will typically be administered in a pharmaceutically acceptable dosage form via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and / or nasal route and / or via inhalation. Depending upon the disease and patient to be treated and the route of administration, the compositions may be administered at varying doses. In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient are administered orally.Dosage forms suitable for oral use form one aspect of the specification. In embodiments, the specification provides a solid oral dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient are administered orally. In embodiments, the solid oral dosage form is a tablet.

[0464] The compositions of the specification may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0465] Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents; granulating and disintegrating agents; binding agents; and lubricating agents. Tablet formulations may be uncoated or coated using conventional coating agents and procedures well known in the art.

[0466] Further information regarding formulations is described in, for example, Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0467] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.

[0468] Further information regarding routes of administration and dosage regimes are described in, for example, Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0469] Combinations

[0470] A compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in conjunction with a second active agent for the prophylaxis or treatment of the diseases described herein. Therefore, in embodiments specification provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a second active agent.

[0471] Administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the second active agent may be concurrent, sequential or simultaneous. Combinations described herein may also be administered with a further active agent or agents.Kits

[0472] In embodiments, the specification provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and instructions for their use in prophylaxis or treatment, such as in the prophylaxis or treatment of the diseases described herein.

[0473] Processes

[0474] Compounds of formula (I) and their pharmaceutically acceptable salts thereof may be prepared according to conventional methods known to the skilled person. In embodiments, the specification provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is obtainable by the methods disclosed in the " Examples" section.

[0475] Intermediates

[0476] In a further aspect the specification provides intermediates used in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts, such as those disclosed in the " Examples" section. In embodiments, the specification provides an intermediate as disclosed in the " Examples" section, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

[0477] Clauses

[0478] The present specification may be further defined by the following clauses:

[0479] Clause 1. A compound of formula (I):

[0480]

[0481] wherein:

[0482] R1is C1-4alkyl, C1-4haloalkyl or phenyl; wherein said phenyl may be substituted by one or two R1a;

[0483] each Rlais independently halo, CN, Ci.4alkyl or Ci.4haloalkyl;

[0484] n is 0, 1 or 2;

[0485] each R2is independently halo or OH;

[0486] m is 1 or 2;

[0487] R10is H, C1-4alkyl or C1-4haloalkyl;

[0488] R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C1-4alkylene(OH); orR11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0489] each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0490] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0491] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0492] B is a 3-7 membered heterocycloalkyl, 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 8-10 membered bicyclic heteroaryl, each of which may be independently substituted by one or two R30;

[0493] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, C(O)NR30cR30d, NR30eC(O)R30f, S(O)2NR30gR30h, NR30iS(O)2R30j, Ci.4alkylene(CN), Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl); wherein when R30is Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl), said C3-6cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one Ci-4alkyl, Ci-4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy or C(O)Ci.4alkyl;

[0494] wherein when B is a 3-7 membered heterocycloalkyl or 8-10 membered bicyclic heteroaryl, each R30may additionally be =0; and

[0495] R30a, R30b, R30c, R30d, R30e, R30f, R30g, R30h, R30iand R30jare each independently H, C1-4alkyl or C1-4haloalkyl; or a pharmaceutically acceptable salt thereof.

[0496] Clause 2. The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R1is Ci-4alkyl.

[0497] Clause 3. The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R1is Ci.4haloalkyl.

[0498] Clause 4. The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R1is phenyl.

[0499] Clause 5. The compound or pharmaceutically acceptable salt thereof according to clause 1 or 4, wherein the phenyl is substituted by one or two (such as one) R1a.

[0500] Clause 6. The compound or pharmaceutically acceptable salt thereof according to clause 5, wherein at least one R1ais halo, such as F.Clause 7. The compound or pharmaceutically acceptable salt thereof according to clause 5 or 6, wherein at least one R1ais CN.

[0501] Clause 8. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 5 to 7, wherein at least one Rlais Ci-4alkyl.

[0502] Clause 9. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 5 to 8, wherein at least one Rlais Ci.4haloalkyl.

[0503] Clause 10. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1, 4 or 5, wherein R1is phenyl substituted by one R1a, and R1ais F or CN.

[0504] Clause 11. The compound or pharmaceutically acceptable salt thereof according to clause 1 or 4, wherein R1is unsubstituted phenyl.

[0505] Clause 12. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 11, wherein n is 0.

[0506] Clause 13. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 11, wherein n is 1.

[0507] Clause 14. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 11, wherein n is 2.

[0508] Clause 15. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 11, 13 or 14, wherein each R2is independently halo (such as F).

[0509] Clause 16. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 11, 13 or 14, wherein each R2is independently OH.

[0510] Clause 17. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 16, wherein m is 1.

[0511] Clause 18. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 17, wherein m is 2.Clause 19. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 18, wherein R10is H.

[0512] Clause 20. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 18, wherein R10is Ci-4alkyl, such as methyl.

[0513] Clause 21. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 18, wherein R10is Ci.4haloalkyl.

[0514] Clause 22. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 18, wherein R10is H or Ci.4alkyl (such as methyl).

[0515] Clause 23. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22, wherein R11and R12are each independently H, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci-4haloalkoxy or Ci.4alkylene(OH).

[0516] Clause 24. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is H.

[0517] Clause 25. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is Ci-4alkyl, such as methyl.

[0518] Clause 26. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is Ci.4haloalkyl.

[0519] Clause 27. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is Ci.4alkoxy, such as CH2OMe.

[0520] Clause 28. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is Ci.4haloalkoxy.

[0521] Clause 29. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is Ci.4alkylene(OH).

[0522] Clause 30. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 29, wherein R12is H.Clause 31. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 29, wherein R12is Ci-4alkyl, such as methyl.

[0523] Clause 32. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 29, wherein R12is Ci.4haloalkyl.

[0524] Clause 33. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 29, wherein R12is Ci.4alkoxy.

[0525] Clause 34. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 29, wherein R12is Ci.4haloalkoxy.

[0526] Clause 35. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 29, wherein R12is Ci.4alkylene(OH).

[0527] Clause 36. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11and R12are each H.

[0528] Clause 37. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11and R12are each Ci.4alkyl (such as methyl).

[0529] Clause 38. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 23, wherein R11is C1-4alkoxy (such as CH2OMe) and R12is H.

[0530] Clause 39. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22, wherein R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl.

[0531] Clause 40. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39, wherein R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl, such as cyclohexyl, cyclobutyl or cyclopropyl, for example cyclopropyl.

[0532] Clause 41. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39, wherein R11and R12together with the carbon atom to which they are attached, form a 3-7 membered heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.Clause 42. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39, wherein R11and R12together with the carbon atom to which they are attached, form an oxetanyl, such as a 3-oxetanyl.

[0533] Clause 43. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 42, wherein R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7 membered heterocycloalkyl which are each independently substituted by one or two (such as one) R13.

[0534] Clause 44. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 43, wherein at least one R13is halo, such as F.

[0535] Clause 45. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 44, wherein at least one R13is Ci-4alkyl, such as methyl.

[0536] Clause 46. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 45, wherein at least one R13is Ci.4haloalkyl.

[0537] Clause 47. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 46, wherein at least one R13is Ci.4alkoxy, such as OMe.

[0538] Clause 48. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 47, wherein at least one R13is Ci.4haloalkoxy.

[0539] Clause 49. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22 or 39 to 48, wherein R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7 membered heterocycloalkyl, each of which are unsubstituted.

[0540] Clause 50. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22, wherein R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which is:such as:

[0541]

[0542] wherein denotes the point of attachment to N(R10), and denotes the point of attachment to A.

[0543] Clause 51. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50, wherein A is -CEC-.

[0544] Clause 52. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50, wherein A is phenyl.

[0545] Clause 53. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50, wherein A is a 5-6 membered monocyclic heteroaryl.

[0546] Clause 54. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 53, wherein A is a 5-membered monocyclic heteroaryl, such as pyrazolyl or triazolyl.

[0547] Clause 55. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 53, wherein A is a 6-membered monocyclic heteroaryl, such as pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0548] Clause 56. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 55, wherein the phenyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one or two (such as one) R20.

[0549] Clause 57. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 56, wherein at least one R20is CN.Clause 58. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 57, wherein at least one R20is halo, such as Cl or F.

[0550] Clause 59. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 58, wherein at least one R20is Ci-4alkyl, such as methyl or ethyl.

[0551] Clause 60. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 59, wherein at least one R20is Ci.4haloalkyl, such as CF3.

[0552] Clause 61. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 60, wherein at least one R20is Ci.4alkoxy, such as OMe.

[0553] Clause 62. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 61, wherein at least one R20is Ci.4haloalkoxy.

[0554] Clause 63. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 56, wherein the phenyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one or two (such as one) R20, and each R20is independently CN, Cl, F, methyl, ethyl, CF3, OCF3 or OCHF2.

[0555] Clause 64. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 56, wherein A is phenyl or 5-6 membered monocyclic heteroaryl (such as pyridyl, pyrimidinyl or pyridazinyl, for example pyridyl), each of which are independently substituted by one R20, and R20is CN, Cl, F, methyl, ethyl, CF3, OCF3or OCHF2.

[0556] Clause 65. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50 or 52 to 55, wherein the phenyl and 5-6 monocyclic heteroaryl are each independently unsubstituted.

[0557] Clause 66. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 50, wherein A is:OMe

[0558] such as:

[0559]

[0560]

[0561] wherein denotes the point of attachment to C(R11)(R12), and denotes the point of attachment to B.

[0562] Clause 67. The compound or pharmaceutically acceptable salt thereof according to any one of

[0563] clauses 1 to 66, wherein

[0564]

[0565] A isClause 68. The compound or pharmaceutically acceptable salt thereof according to any one of

[0566] clauses 1 to 66, wherein

[0567]

[0568] A is

[0569] Clause 69. The compound or pharmaceutically acceptable salt thereof according to any one of

[0570] clauses 1 to 66, wherein

[0571]

[0572] A is

[0573] Clause 70. The compound or pharmaceutically acceptable salt thereof according to any one of

[0574] clauses 1 to 66, wherein

[0575]

[0576] A is

[0577] Clause 71. The compound or pharmaceutically acceptable salt thereof according to any one of Me

[0578] clauses 1 to 66, wherein

[0579]

[0580] A is

[0581] Clause 72. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is a 3-7 membered heterocycloalkyl, such as a 6-membered heterocycloalkyl, for example morpholinyl or piperazinyl, for example:

[0582]

[0583] Clause 73. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is a 5-membered monocyclic heteroaryl, such as pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl or thiadiazolyl, for example pyrazolyl.

[0584] Clause 74. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is phenyl.

[0585] Clause 75. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is pyridyl.Clause 76. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is pyridazinyl.

[0586] Clause 77. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is pyrimidinyl.

[0587] Clause 78. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is pyrazinyl.

[0588] Clause 79. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein B is an 8-10 membered bicyclic heteroaryl, such as:

[0589]

[0590] Clause 80. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein B is substituted by one or two (such as one) R30.

[0591] Clause 81. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is CN.

[0592] Clause 82. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is halo, such as F.

[0593] Clause 83. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Ci-4alkyl, such as methyl.Clause 84. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Ci.4haloalkyl, such as CHF2.

[0594] Clause 85. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Ci.4alkoxy, such as OMe.

[0595] Clause 86. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Ci.4haloalkoxy, such as OCHF2.

[0596] Clause 87. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is NR30aR30b, such as NH2, NHMe or NHEt.

[0597] Clause 88. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is C(O)NR30cR30d, such as C(O)NH2.

[0598] Clause 89. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is NR30eC(O)R30f.

[0599] Clause 90. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is S(O)2NR30gR30h, such as S(O)2NH2.

[0600] Clause 91. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is NR30iS(O)2R30j.

[0601] Clause 92. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Ci.4alkylene(CN), such as CH2CN or CH2CH2CN.

[0602] Clause 93. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Co-4alkylene(C3-6cycloalkyl).

[0603] Clause 94. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Co-4alkylene(3-7 membered heterocycloalkyl), such as 3-7 membered heterocycloalkyl, for example oxetanyl, thietanyl 1,1-dioxide or piperidinyl.

[0604] Clause 95. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 78, wherein at least one R30is Co-4alkylene(5-6 membered monocyclic heteroaryl).Clause 96. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 72 or 79, wherein at least one R30is =0.

[0605] Clause 97. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 or 93 to 95, wherein when at least one R30is Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl), said Cs-ecycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one Ci.4alkyl (such as methyl), Ci.4haloalkyl, Ci.4alkoxy (such as CH2CH2OMe), Ci-4haloalkoxy or C(O)Ci.4alkyl (such as C(O)Me).

[0606] Clause 98. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 or 93 to 95, wherein when at least one R30is Co-4alkylene(C3-6cycloalkyl), Co-4alkylene(3-7 membered heterocycloalkyl) or Co-4alkylene(5-6 membered monocyclic heteroaryl), said Cs-ecycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl are each independently unsubstituted.

[0607] Clause 99. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein:

[0608] B is a 5-membered monocyclic heteroaryl (such as pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl or thiadiazolyl, for example pyrazolyl) substituted by one or two R30;

[0609] each R30is independently CN, halo (such as F), Ci.4alkyl (such as methyl), Ci.4haloalkyl (such as CHF2), Ci-4alkoxy (such as OMe), NR30aR30b(such as NH2), Ci.4alkylene(CN) (such as CH2CN or CH2CH2CN) or Co-4alkylene(3-7 membered heterocycloalkyl) (such as oxetanyl or piperidinyl); and

[0610] said 3-7 membered heterocycloalkyl may be substituted by one Ci.4alkyl (such as methyl) or C(O)Ci.4alkyl (such as C(O)Me).

[0611] Clause 100. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71 or 99, wherein B is:

[0612]

[0613] ; such as:

[0614]

[0615] or Clause 101. The compound or pharmaceutically acceptable salt thereof according to any one of

[0616] clauses 1 to 71, 99 or 100, wherein B

[0617]

[0618] is

[0619] Clause 102. The compound or pharmaceutically acceptable salt thereof according to any one of

[0620] clauses 1 to 71, 99 or 100, wherein

[0621]

[0622] B is

[0623] Clause 103. The compound or pharmaceutically acceptable salt thereof according to any one of

[0624] clauses 1 to 71, 99 or 100, wherein B

[0625]

[0626] isClause 104. The compound or pharmaceutically acceptable salt thereof according to any one of

[0627] clauses 1 to 71, 99 or 100, wherein B is

[0628]

[0629] Clause 105. The compound or pharmaceutically acceptable salt thereof according to any one of

[0630] clauses 1 to 71, 99 or 100, wherein B is

[0631]

[0632] Clause 106. The compound or pharmaceutically acceptable salt thereof according to any one of

[0633] clauses 1 to 71, 99 or 100, wherein B is

[0634]

[0635] Clause 107. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71, wherein:

[0636] B is pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl (such as pyrimidinyl) substituted by one or two R30; and each R30is independently CN, halo (such as F), Ci.4alkyl (such as methyl), Ci.4haloalkyl (such as CHF2), Ci-4alkoxy (such as OMe), NR30aR30b(such as NH2) or C(O)NR30cR30d(such as C(O)NH2).

[0637] Clause 108. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 71 or 107, wherein B is:

[0638]

[0639] Et I

[0640] such as:

[0641]

[0642] Clause 109. The compound or pharmaceutically acceptable salt thereof according to any one of

[0643] clauses 1 to 71, 107 or 108, wherein B is

[0644]

[0645] Clause 110. The compound or pharmaceutically acceptable salt thereof according to any one of

[0646]

[0647] clauses 1 to 71, 107 or 108, wherein B is0Me

[0648] Clause 111. The compound or pharmaceutically acceptable salt thereof according to any one of

[0649] clauses 1 to 71, 107 or 108, wherein B is

[0650]

[0651] Clause 112. The compound or pharmaceutically acceptable salt thereof according to any one of

[0652]

[0653] clauses 1 to 71, 107 or 108, wherein B isMe

[0654] Clause 113. The compound or pharmaceutically acceptable salt thereof according to any one of

[0655] clauses 1 to 71, 107 or 108, wherein B is

[0656]

[0657] Clause 114. The compound or pharmaceutically acceptable salt thereof according to any one of

[0658] clauses 1 to 71, 107 or 108, wherein B is

[0659]

[0660] Clause 115. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 79, wherein B is unsubstituted.

[0661] Clause 116. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, wherein the carbon bearing R1has the following stereochemistry:

[0662] R1

[0663]

[0664] Clause 117. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, wherein the carbon bearing R1has the following stereochemistry:

[0665] R1

[0666]

[0667] Clause 118. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, which is a compound of formula (IA):

[0668]

[0669] wherein:

[0670] R1is Ci-4alkyl or phenyl; wherein said phenyl may be substituted by one or two Rla;

[0671] each Rlais independently halo or CN;

[0672] n is 0, 1 or 2;

[0673] each R2is independently halo or OH;

[0674] m is 1 or 2;R10is H or Ci-4alkyl;

[0675] R11and R12are each independently H, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy or Ci.4haloalkoxy; or

[0676] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0677] each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0678] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0679] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0680] B is a 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one or two R30;

[0681] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, C(O)NR30cR30d, S(O)2NR30gR30h, Ci.4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl); wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy or C(O)Ci.4alkyl; and

[0682] R30a, R30b, R30c, R30d, R30gand R30hare each independently H, Ci.4alkyl or Ci.4haloalkyl;

[0683] or a pharmaceutically acceptable salt thereof.

[0684] Clause 119. The compound or pharmaceutically acceptable salt thereof according to clause 118, which is a compound of formula (IA-1):

[0685]

[0686] or a pharmaceutically acceptable salt thereof.

[0687] Clause 120. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, which is a compound of formula (IB):

[0688]

[0689] wherein:

[0690] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0691] each Rlais independently halo or CN;

[0692] n is 0, 1 or 2;

[0693] each R2is independently halo or OH;

[0694] m is 1;

[0695] R10is H or Ci-4alkyl;

[0696] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0697] each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0698] A is phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0699] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0700] B is a 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one or two R30;

[0701] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, C(O)NR30cR30d, S(O)2NR30gR30h, Ci.4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl); wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy or C(O)Ci.4alkyl; and

[0702] R30a, R30b, R30c, R30dR30g, and R30hare each independently H, Ci.4alkyl or Ci.4haloalkyl;

[0703] or a pharmaceutically acceptable salt thereof.

[0704] Clause 121. The compound or pharmaceutically acceptable salt thereof according to clause 120, which is a compound of formula (IB-1):

[0705]

[0706] or a pharmaceutically acceptable salt thereof.

[0707] Clause 122. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, which is a compound of formula (IC):

[0708]

[0709] wherein:

[0710] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0711] each Rlais independently halo or CN;

[0712] R10is H or Ci-4alkyl;

[0713] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;

[0714] each R13is independently halo or Ci-4alkyl;

[0715] A is phenyl or 6 membered monocyclic heteroaryl; wherein said phenyl or 6 membered monocyclic heteroaryl may each be independently substituted by one R20;

[0716] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;

[0717] B is pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl, thiadiazolyl or pyrimidinyl, each of which may be independently substituted by one or two R30;

[0718] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, Ci-4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl);

[0719] wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy or C(O)Ci.4alkyl; and

[0720] R30aand R30bare each independently H, Ci.4alkyl or Ci.4haloalkyl;

[0721] or a pharmaceutically acceptable salt thereof.

[0722] Clause 123. The compound or pharmaceutically acceptable salt thereof according to clause 122, which is a compound of formula (IC-1):

[0723]

[0724] or a pharmaceutically acceptable salt thereof.Clause 124. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, which is a compound of formula (ID):

[0725]

[0726] wherein:

[0727] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0728] each Rlais independently halo or CN;

[0729] n is 0, 1 or 2;

[0730] each R2is independently halo or OH;

[0731] m is 1 or 2;

[0732] R10is H or Ci-4alkyl;

[0733] R11and R12are each independently H, Ci.4alkyl, Ci.4haloalkyl, Ci.4alkoxy or Ci.4haloalkoxy; or R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7

[0734] membered heterocycloalkyl which is

[0735]

[0736] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0737] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; and

[0738]

[0739] or a pharmaceutically acceptable salt thereof.

[0740] Clause 125. The compound or pharmaceutically acceptable salt thereof according to clause 124, which is a compound of formula (ID-1):

[0741]

[0742] or a pharmaceutically acceptable salt thereof.

[0743] Clause 126. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 115, which is a compound of formula (IE):

[0744]

[0745] (IE),

[0746] wherein:

[0747] R1is phenyl; wherein said phenyl may be substituted by one or two Rla;

[0748] each Rlais independently halo or CN;

[0749] n is 0, 1 or 2;

[0750] each R2is independently halo or OH;

[0751] m is 1 or 2;

[0752] R10is H or Ci-4alkyl;

[0753] R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; or R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which is

[0754]

[0755] A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;

[0756] each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; and

[0757]

[0758] or a pharmaceutically acceptable salt thereof.

[0759] Clause 127. The compound or pharmaceutically acceptable salt thereof according to clause 126, which is a compound of formula (IE-1):

[0760]

[0761] or a pharmaceutically acceptable salt thereof.

[0762] Clause 128. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 127, wherein:

[0763] B is pyrimidinyl which may be substituted by one or two R30;

[0764] each R30is independently CN, Ci-4alkyl, Ci.4alkoxy or NR30aR30b;

[0765] R30aand R30bare each independently H or Ci-4alkyl;

[0766] A is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one or two R20;

[0767] each R20is halo or Ci-4alkyl;

[0768] R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13; and each R13is halo.

[0769] Clause 129. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 127, wherein:

[0770] B is pyrazolyl which may be substituted by or two R30;

[0771] each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl); wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be substituted by one Ci-4alkyl, Ci.4alkoxy or C(O)Ci-4alkyl;

[0772] A is phenyl, pyridyl, pyrimidinyl or pyrazinyl, each of which may be independently substituted by one R20;

[0773] R20is Ci-4alkyl;

[0774] R11and R12together with the carbon atom to which they are attached, form a Cs-ecycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one R13; and

[0775] each R13is Ci-4alkyl.

[0776] Clause 130. The compound or pharmaceutically acceptable salt thereof according to clause 1, which is:

[0777] (5S)- / V-{3-[4-(6-cyanopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(6-aminopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0778] (5S)- / V-{3-[4-(5-aminopyrazin-2-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0779] (5S)- / V-(3-{4-[2-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0780] (5S)-N-{3-[4-(6-amino-5-methylpyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0781] (5S)-N-(3-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0782] (5S)-N-{3-[4-(2-fluoropyridin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0783] (5S)-N-{3-[4-(2-amino-4-methylpyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0784] (5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyridin-8-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0785] (5S)-N-[3-(4'-carbamoyl-3'-fluoro[1,1'-biphenyl]-4-yl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0786] (5S)-N-{3-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0787] (5S)-5-phenyl-N-{3-[4-(lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole- 2-carboxamide;

[0788] (5S)-N-{3-[4-(2-aminopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0789] (5S)-5-phenyl-N-[3-(4'-sulfamoyl[1,1'-biphenyl]-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0790] (5S)-N-{3-[4-(2-oxo-2,3-dihydro-1H-indol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0791] (5S)-N-{3-[4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0792] (5S)-N-{3-[4-(3-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0793] (5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0794] (5S)-N-{3-[4-(2-methoxypyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(cyanomethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0795] (5S)-N-(3-{4-[(3R)-3-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0796] (5S)-5-phenyl-N-{3-[4-(pyrimidin-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0797] (5S)-5-phenyl-N-{3-[4-(pyridin-3-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0798] (5S)-N-(3-{4-[6-(difluoromethyl)pyridin-3-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0799] (5S)-N-{3-[4-(5-methylpyridazin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0800] (5S)-N-(3-{4-[(3S)-3-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0801] (5S)-N-(3-{4-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0802] (5S)-N-{3-[4-(2-methoxypyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0803] (5S)-N-(3-{4-[l-(l-acetylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0804] (5S)-N-{3-[4-(6-fluoropyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0805] (5S)-N-(3-{4-[l-(oxetan-3-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0806] (5S)-N-{3-[4-(2-methyl-l,3-thiazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0807] (5S)-N-(3-{4-[l-(l-acetylpiperidin-4-yl)-5-methyl-lH-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0808] (5S)-5-phenyl-N-{3-[4-(l,3-thiazol-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0809] (5S)-N-{3-[4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0810] (5S)-N-(3-{4-[l-(2-cyanoethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0811] (5S)-N-{3-[4-(5-fluoro-l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(l,l-dioxo-lX6-thietan-3-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0812] (5S)-N-{3-[4-(3-cyanopyrazolo[l,5-a]pyrimidin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0813] (5S)-5-phenyl-N-{3-[4-(lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0814] (5S)- / V-{3-[4-(l-methyl-lH-imidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0815] (5S)-N-{3-[4-(lH-benzotriazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0816] (5S)-N-{3-[4-(l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0817] (5S)-N-{3-[4-(1,3-dimethyl-1H-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0818] (5S)-N-{3-[4-(lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0819] (5S)-N-{3-[4-(l,2-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0820] (5S)-N-{3-[4-(3-methoxy-l-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0821] (5S)-N-{3-[4-(2-amino-4-methoxypyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0822] (5S)-N-{3-[4-(2-amino-lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0823] (5S)- / V-{3-[4-(5-amino-lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0824] (5S)-N-{3-[4-(2-aminopyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0825] (5S)-N-{3-[4-(6-aminopyridazin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0826] (5S)-N-{3-[4-(2-amino[l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0827] (5S)-N-{3-[4-(l,4-dimethyl-lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0828] (5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyrimidin-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0829] (5S)-N-{3-[4-(lH-imidazo[4,5-b]pyridin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0830] (5S)-N-{3-[4-(5-cyano-l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0831] (5S)-N-{3-[4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0832] (5S)-N-{3-[4-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0833] (5S)-N-{3-[4-(6-amino-5-methylpyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0834] (5S)-N-{3-[4-(2-amino-4-ethylpyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0835] (5S)-N-{3-[4-(2,4-diaminopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0836] (5S)-N-(3-{4-[2-amino-4-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0837] (5S)-N-{3-[4-(5-methyl-l,3-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0838] (5S)-N-(3-{4-[2-(ethylamino)-4-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0839] (5S)-N-{3-[4-(2-amino-5-methyl-l,3-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0840] (5S)- / V-{3-[4-(3H-imidazo[4,5-b]pyridin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0841] (5S)-N-{3-[4-(4-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0842] (5S)-N-{3-[4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0843] (5S)-5-phenyl- / V-{3-[4-(l,3,4-thiadiazol-2-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0844] (5S)- / V-{3-[4-(6-aminopyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0845] (5S)- / V-{3-[4-(2-amino-4-cyanopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{4-[(3RS)-3-carbamoylpiperidin-l-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0846] (5S)-N-{3-[4-(3-oxopiperazin-l-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0847] (5S)-N-{3-[4-(morpholin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0848] (5S)- / V-(3-{4-[5-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0849] (5S)-N-{3-[4-(5-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0850] (5S)- / V-{3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0851] (5S)-N-{3-[4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0852] (5S)- / V-{3-[4-(4-amino-l-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0853] (5S)-N-[3-(4-{1-[1-(2-methoxyethyl)piperidin-4-yl]-1H-pyrazol-4-yl}phenyl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0854] (5S)- / V-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0855] (5S)- / V-{3-[6-(2-aminopyrimidin-5-yl)pyridazin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0856] (5S)-N-{3-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0857] (5S)-N-{1-[6-(6-amino-4-methylpyridin-3-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0858] (5S)-N-{1-[6-(2-amino-4-methoxypyrimidin-5-yl)pyridazine-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0859] (5S)-N-{1-[6-(6-amino-4-methoxypyridin-3-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0860] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0861] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0862] (5S)-N-{1-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(3-methyl-1H-pyrazol-4-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0863] (5S)-N-{1-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0864] (5S)-N-{1-[6-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0865] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0866] (5S)-N-[l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0867] (5S)-N-[l-(2'-amino-4'-methyl[5,5'-bipyrimidin]-2-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0868] (5S)-N-[l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0869] (5S)-N-{1-[4-(2-aminopyrimidin-5-yl)-3-methylphenyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0870] (5S)-N-{1-[4-(2-aminopyrimidin-5-yl)-2-methylphenyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0871] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0872] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0873] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0874] (5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0875] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0876] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0877] (5S)-N-(l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0878] (5S)-N-[l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0879] (5S)-N-(l-{5-methyl-6-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0880] (5S)-N-(1-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0881] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0882] (5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0883] (5S)- / V-(l-{5-methyl-6-[l-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0884] (5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0885] (5S)-N-(3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0886] (5S)-N-{3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0887] (5S)-N-{3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0888] (5S)-N-{3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0889] (5S)- / V-{3-[5-methyl-6-(5-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0890] (5S)- / V-(3-{6-[l-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0891] (5S)- / V-(3-{6-[l-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0892] (5S)-N-(3-{5-methyl-6-[1-(2H3)methyl-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0893] (5S)-N-({6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}methyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0894] (5S)-N-[{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0895] (5S)-N-[(lR)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0896] (5S)-N-[(lS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0897] (5S)-N-[(lR,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0898] (5S)-N-[(lS,2R)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0899] (5S)-N-(l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutyl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0900] (5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0901] (5S)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0902] (5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0903] (5S)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0904] (5S)-5-(3-cyanophenyl)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0905] (5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0906] (5S)- / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0907] (5S)- / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0908] (5R)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0909] (5R)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0910] (5S)- / V-(3-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylphenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0911] (5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0912] (5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methyl-l-oxo-lX5-pyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0913] (5S)-N-{1-[1-(2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazol-4-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(3-{1-[2-(difluoromethyl)-2H-indazol-5-yl]-1H-pyrazol-4-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0914] (5S)- / V-{3-[l-(2-amino[l,2,4]triazolo[l,5-a]pyridin-7-yl)-1H-pyrazol-4-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0915] (5S)-N-(3-{1-[2-(difluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]-1H-pyrazol-4-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0916] (5S)-N-(1-{1-[4-(difluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0917] (5S)- / V-(l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0918] (5S)- / V-(3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0919] (5S)-N-{1-[(2-aminopyrimidin-5-yl)ethynyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0920] (5S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0921] (5S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-5-(3-cyanophenyl)-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0922] (5S)-5-(3-cyanophenyl)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0923] (5S)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0924] (5S)- / V-[(lR)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0925] (5S)- / V-[(lS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0926] (5S)- / V-[(lR)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0927] (5S)- / V-[(lS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0928] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0929] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclohexyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0930] (5S)-N-(4-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxan-4-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{(lS)-l-[4-(2-aminopyrimidin-5-yl)phenyl]propyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0931] (5S)-N-{(3R)-3-[4-(2-aminopyrimidin-5-yl)phenyl]oxolan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0932] (5S)-N-{(3S)-3-[4-(2-aminopyrimidin-5-yl)phenyl]oxolan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0933] (5S)-N-[(lR)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methoxyethyl]-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0934] (5S)-N-[(lS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methoxyethyl]-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0935] (5S)-N-{1-[4-(2-aminopyrimidin-5-yl)phenyl]-3,3-difluorocyclobutyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0936] (5S,7S)- / V-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0937] (5S,7S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0938] (5S,7S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0939] (5S,7S)-N-{1-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0940] (5S,7S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0941] (5S,7R)-N-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0942] (5S)-N-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0943] (5S)-N-(l-{3-chloro-4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0944] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methoxypyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0945] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methoxyphenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0946] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3,5-difluorophenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0947] (5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluoropyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0948] (5S)-N-(l-{3-cyano-4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0949] (5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0950] (5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethoxy)phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0951] (5S)- / V-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylpyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0952] (5S)- / V-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3,5-dimethylphenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;

[0953] (5R)-N-(1-{3-(difluoromethoxy)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0954] (5S)-N-(1-{3-(difluoromethoxy)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0955] (5S)-N-(1-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

[0956] (5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluoro-3-methoxyphenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; or

[0957] (5S)-N-(1-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyrimidin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide,

[0958] or a pharmaceutically acceptable salt of any one thereof.

[0959] Clause 131. The compound according to any one of clauses 1 to 130.

[0960] Clause 132. The pharmaceutically acceptable salt of a compound according to any one of clauses 1 to 130.

[0961] Clause 133. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132, and at least one pharmaceutically acceptable excipient.

[0962] Clause 134. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132, or the pharmaceutical composition according to clause 133, for use as a medicament.Clause 135. The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132, or the pharmaceutical composition according to clause 133, for use in the treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0963] Clause 136. Use of a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132, or the pharmaceutical composition according to clause 133, in the manufacture of a medicament for the treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0964] Clause 137. A method of treating a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect, comprising administering a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132, or a pharmaceutical composition according to clause 133.

[0965] Clause 138. The compound for use, pharmaceutically acceptable salt for use, pharmaceutical composition for use, use or method according to any one of clauses 134 to 137, wherein the disease is an inflammatory disease, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune lymphoproliferative syndrome (APS), arthritis (such as osteoarthritis), rheumatoid arthritis (RA), non-communicable inflammatory skin diseases (ncISD) (such as psoriasis (PsO) or atopic dermatitis (AD)), asthma, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), systemic sclerosis (SSc), chronic obstructive pulmonary disease (COPD), lysosomal storage disorders, sepsis, acute kidney disease (AKD), chronic kidney disease (CKD), Sjogren's syndrome (SjS), celiac disease, atherosclerosis, Crohn's disease (CD), colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematous (SLE), lupus or other forms of nephritis, Parkinson's disease or ulcerative colitis (UC).

[0966] Clause 139. The compound for use, pharmaceutically acceptable salt for use, pharmaceutical composition for use, use or method according to any one of clauses 107 to 110, wherein the disease is an inflammatory disease of the intestines, such as Crohn's disease or ulcerative colitis.

[0967] Clause 140. A combination comprising a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132, and a second active agent.

[0968] Clause 141. A kit comprising a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 to 132 and instructions for their use in prophylaxis or treatment, such as in theprophylaxis or treatment of a disorder in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

[0969] Experimental

[0970] The specific examples included herein are for illustrative purposes only and are not to be considered as limiting to this disclosure. These examples provide guidance to the skilled person in the art to prepare and use the compounds, compositions, and methods of the present disclosure. Moreover, the compounds, compositions, and methods provided herein have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration. It will be apparent to those skilled in the art that the disclosure is susceptible to additional embodiments and that certain of the details described herein may be varied without departing from the basic principles of the disclosure.

[0971] In the following Examples, chemical shifts are expressed as parts per million (ppm) units.

[0972] Coupling constants (J), where accounted for, are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m, (multiplet), br (broad). Column chromatography was performed on silica gel unless otherwise stated. The naming program used is ACD / ChemSketch 2020.2.0. Vibrational circular dichroism was used for some examples to indicate absolute configuration.

[0973] Intermediates utilised in the synthesis of compounds of the present disclosure are recited in the following table:

[0974] Int Structure IUPAC Name

[0975] 1 o (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylic acid

[0976] 2 o (5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazole-2-carboxylic acid

[0977] 3 (5S)- / V-[3-(4-bromophenyl)oxetan-3-yl]-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide

[0978] 4 (5S)-5-phenyl- / V-{3-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl}-6,7- Q p

[0979] dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxamide

[0980] 5 3-[4-(5-methyl-2H-1,2,3-triazol-4- yl)phenyl]oxetan-3-aminium trifluoroacetate

[0981]

[0982] 3-[4-(l74-dimethyl-lH-l7273-triazol-5- □0H3N® U ' yl)phenyl]oxetan-3-aminium trifluoroacetate

[0983] 3-[4-(5-methyl-lH-l,2,3-triazol-l- yl)phenyl]oxetan-3-aminium chloride

[0984] o o o

[0985] h 3-[4-(l-methyl-4-nitro-lH-pyrazol-5- Azw yl)phenyl]oxetan-3-amine

[0986] (5S)-5-phenyl- / V-(3-{4-[l-(piperidin-4-yl)-lH- Q p pyrazol-4-yl]phenyl}oxetan-3-yl)-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[0987] 5-[6-(l-aminocyclopropyl)pyridazin-3- yl]pyrimidin-2-amine

[0988] 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4- p

[0989] methylpyrimidin-2-amine

[0990] w

[0991] :

[0992] 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4- methylpyridin-2-amine

[0993] 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4- methoxypyrimidin-2-amine

[0994] 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4- methoxypyridin-2-amine

[0995] 5-[5-(l-aminocyclopropyl)pyridin-2- yl]pyrimidin-2-amine

[0996] 5-[6-(l-aminocyclopropyl)pyridin-3- yl]pyrimidin-2-amine

[0997] l-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2- M yl]cyclopropan-l-aminium chloride

[0998]

[0999] l-[5-(3-methyl-lH-pyrazol-4-yl)pyridin-2- yl]cyclopropan-l-aminium chloride

[1000] l-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3- yl]cyclopropan-l-aminium chloride

[1001] l-[6-(3-methyl-lH-pyrazol-4-yl)pyridin-3- II \

[1002] o yl]cyclopropan-l-aminium chloride

[1003] l-[5-(2-aminopyrimidin-5-yl)pyrazin-2- yl]cyclopropan-l-aminium formate

[1004] l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropan- 4©©

[1005] 1-aminium trifluoroacetate

[1006] IT 2'-(l-aminocyclopropyl)-4-m ethyl [5,5'- V bipyrimidin]-2-amine

[1007] H l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropan- M 1-aminium chloride

[1008] w

[1009] Q

[1010] Q

[1011] w

[1012] l-[4-(2-aminopyrimidin-5-yl)-3- methylphenyl]cyclopropan-l-aminium chloride l-[4-(2-aminopyrimidin-5-yl)-2-CLH3N? XJ ITJ methylphenyl]cyclopropan-l-aminium chloride 5-[5-(l-aminocyclopropyl)-3-methylpyridin-2- yl]pyrimidin-2-amine

[1013] IT 5-[6-(l-aminocyclopropyl)-2-methylpyridin-3- ^A yl]pyrimidin-2-amine

[1014] l-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2- yl]cyclopropan-l-aminium chloride

[1015] N^NH2

[1016] 1-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-C|S H N^N^V 2-yl]cyclopropan-l-aminium chloride

[1017]

[1018] l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6- methylpyridin-2-yl}cyclopropan-l-aminium chloride

[1019] l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6- methylpyrazin-2-yl}cyclopropan-l-aminium chloride

[1020] tert-butyl [l-(6-bromo-5-methylpyridin-3- yl)cyclopropyl]carbamate

[1021] l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- methylpyridin-3-yl}cyclopropan-l-aminium chloride

[1022] l-(6'-amino-3-methyl[2,3'-bipyridin]-5- yl)cyclopropan-l-aminium chloride

[1023] 4-{4-[5-(l-azaniumylcyclopropyl)-3- methylpyridin-2-yl]-lH-pyrazol-l-yl}-l- Q methylpiperidin-l-ium dichloride

[1024] q W l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5- q q

[1025] o w

[1026] ® XI methylpyridin-3-yl}cyclopropan-l-aminium chloride

[1027] l-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5- methylpyridin-3-yl}cyclopropan-l-amine l-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3- yl]cyclopropan-l-aminium chloride

[1028] l-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3- yl]cyclopropan-l-aminium chloride

[1029] tert-butyl 4-{4-[3-methyl-5-(l-{[(5S)-5-phenyl- X

[1030] 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carbonyl]amino}cyclopropyl)pyridin-2-yl]-lH- Y

[1031] pyrazol-l-yl}piperidine-l-carboxylate

[1032] A 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- methylpyridin-3-yl}oxetan-3-amine

[1033] 3-{5-methyl-6-[l-(trifluoromethyl)-lH-pyrazol- 4-yl]pyridin-3-yl}oxetan-3-amine

[1034]

[1035] 3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5- methylpyridin-3-yl]oxetan-3-amine

[1036] 3-[5-methyl-6-(l-methyl-lH-pyrazol-4- yl)pyridin-3-yl]oxetan-3-amine

[1037] 3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3- o w yl]oxetan-3-amine

[1038] 1

[1039] 3-(6-bromo-5-methylpyridin-3-yl)oxetan-3- amine

[1040] Q & (5S)- / V-[3-(6-bromo-5-methylpyridin-3- A'N-V / " yl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- methylpyridin-3-yl}methanamine

[1041] l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- f. NJ

[1042] H N 0O T^M

[1043] 2 X 5J\ 1F

[1044] methylpyridin-3-yl}(2H2)methanamine O'

[1045] (lRS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]- o

[1046] | ZvNz / ° 5-methylpyridin-3-yl}ethan-l-amine

[1047] 2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- methylpyridin-3-yl}propan-2-amine

[1048] F

[1049] / NA / ^ rac-(lR,2S)-l-{6-[l-(difluoromethyl)-lH-pyrazol- 4-yl]-5-methylpyridin-3-yl}-2- methylcyclopropan-l-amine

[1050] l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- HF

[1051] methylpyridin-3-yl}-3-methoxycyclobutan-l- aminium chloride

[1052] o (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-FCOO pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-Fo X’M-N

[1053] C1M pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid O (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H- vTwHpyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1054]

[1055] (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H- X'M-NOH

[1056] w pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H- ^N'VHpyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid 3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-F

[1057] methylpyridin-2-yl}oxetan-3-amine

[1058] ZNJVK 3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6- methylpyrazin-2-yl}oxetan-3-amine

[1059] (5S)- / V-[3-(4-bromo-3-methylphenyl)oxetan-3- o d

[1060] yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide

[1061] ZNAA / 3-{6-[l-(difluoromethyl)-1H-pyrazol-4- yl]pyridin-3-yl}oxetan-3-amine

[1062] 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- ITF

[1063] methylpyridin-3-yl}- / V-methyloxetan-3-amine (5S)-5-phenyl- / V-[l-(lH-pyrazol-4- Q 6

[1064] X $ yl)cyclopropyl]-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide

[1065] di-tert-butyl (7-bromo[l,2,4]triazolo[l,5- N4 a]pyridin-2-yl)-2-imidodicarbonate

[1066] Q

[1067] (5S)-5-phenyl- / V-[3-(lH-pyrazol-4-yl)oxetan-3- Q 6

[1068] yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole- w

[1069] 2-carboxamide

[1070] 7-bromo-2-(difluoromethyl) [l,2,4]triazolo[l,5- a]pyridine

[1071] l-{l-[4-(difluoromethoxy)phenyl]-lH-l,2,3- H

[1072] 0 triazol-4-yl}cyclopropan-l-aminium trifluoroacetate

[1073] l-{[l-(difluoromethyl)-1H-pyrazol-4- f yl]ethynyl}cyclopropan-l-amine

[1074] ^

[1075]

[1076] 3-{[l-(difluoromethyl)-1H-pyrazol-4- yl]ethynyl}oxetan-3-amine

[1077] NH2l-[(2-aminopyrimidin-5-yl)ethynyl]cyclopropan- W

[1078] 1-aminium trifluoroacetate

[1079] YXQZ

[1080] 5-[6-(3-aminooxetan-3-yl)-2-methylpyridin-3- % yl]pyrimidin-2-amine

[1081] (5S)- / V-[(lRS)-l-(5-bromo-6-methylpyridin-2- yl)ethyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide

[1082] NXK (lRS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]- HYNI 6-methylpyrazin-2-yl}ethan-l-amine

[1083] l-{4-[l-(difluoromethyl)-1H-pyrazol-4- yl]phenyl}cyclobutan-l-amine

[1084] l-{4-[l-(difluoromethyl)-1H-pyrazol-4- „ ^ZT'

[1085] o o yl]phenyl}cyclohexan-l-amine

[1086] Q o o O

[1087] X / ° 4-{4-[l-(difluoromethyl)-1H-pyrazol-4- yl]phenyl}oxan-4-amine

[1088] 5-{4-[(lS)-l-aminopropyl]phenyl}pyrimidin-2- amine

[1089] (3RS)-3-[4-(2-aminopyrimidin-5- yl)phenyl]oxolan-3-aminium chloride, N^1^ZN~( (lRS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]- 5-methylpyridin-3-yl}-2-methoxyethan-l-amine (5S)- / V-[l-(4-bromophenyl)-3,3- difluorocyclobutyl]-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H- sM pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1090]

[1091] (5S,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1092] (5S)-7,7-difluoro-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1093] 5-[4-(3-aminooxetan-3-yl)phenyl]pyrimidin-2- amine

[1094] l-{3-chloro-4-[l-(difluoromethyl)-1H-pyrazol-4- yl]phenyl}cyclopropan-l-aminium chloride l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6- methoxypyridin-2-yl}cyclopropan-l-amine l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3- methoxyphenyl}cyclopropan-l-amine l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3,5- AA difluorophenyl}cyclopropan-l-aminium trifluoroacetate

[1095] ^

[1096] 0 O l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-4- w

[1097] M Q methoxypyridin-2-yl}cyclopropan-l-amine l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3- fluoropyridin-2-yl}cyclopropan-l-aminium chloride

[1098] 1 _N— { l-{3-cyano-4-[l-(difluoromethyl)-1H-pyrazol-4- yl]phenyl}cyclopropan-l-aminium chloride l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3- (trifluoromethyl)phenyl}cyclopropan-l-amine (5S)- / V-{l-[4-bromo-3- A z ' ^“F(trifluoromethoxy)phenyl]cyclopropyl}-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide

[1099] (5S)- / V-[l-(5-bromo-3-methylpyridin-2- <5

[1100] A ^ yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (5S)-A / -[l-(4-bromo-3,5- A-N'VTA dimethylphenyl)cyclopropyl]-5-phenyl-6,7-

[1101]

[1102] dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxamide

[1103] 99 l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-4- H2N.

[1104] methoxypyridin-3-yl}cyclopropan-l-amine

[1105] 100 l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-2-H’NYVO fluoro-3-methoxyphenyl}cyclopropan-l-amine 101 (5S)- / V-[l-(5-bromo-4-methoxypyrimidin-2- ONA_°\

[1106] yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1107]

[1108] Preparation of intermediates 1- 101 is described below.

[1109] Intermediate 1: (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1110]

[1111] Step 1: tert-butyl [(5RS)-2-oxo-5-phenylpyrrolidin-l-yl]carbamate

[1112]

[1113] A

[1114] tert-butyl hydrazinecarboxylate (28.5 g, 215.38 mmol) was added in one portion to a solution of methyl 4-oxo-4-phenylbutanoate (34.5 g, 179.49 mmol) in THF (350 mL) / acetic acid (70.0 mL). The resulting pale yellow solution was stirred at 40°C overnight after which LC-MS indicated complete conversion into the corresponding imine product. To the resulting pale yellow solution at 40 °C was added sodium cyanotrihydroborate (18.1 g, 287 mmol) and the solution was stirred at 40 °C overnight after which LC-MS indicated the reaction was complete. The reaction mixture was then slowly poured into 1.2 L of aq.

[1115] 10 % sodium hydrogen carbonate with vigorous stirring, and after effervescence was completed and pH confirmed neutralization, the mixture was extracted into ethyl acetate (2 x 250 mL). The combined extracts were washed with aq. 10 % sodium hydrogen carbonate (1 x 100 mL) and brine (1 x 50 mL), then dried (magnesium sulphate), filtered and concentrated. The residue was sonicated in t-butyl methyl ether (100 mL) to afford a colourless precipitate, which was collected by filtration, then washed with t-butyl methyl ether (2 x 25 mL) and air-dried to afford the title compound as a colourless powdered solid (26.3 g, 53 %): 1H NMR (500 MHz, CDCl3, 25°C) 6 1.43 (s, 9H), 1.91–2.01 (m, 1H), 2.47–2.63 (m, 3H), 4.91 (s, 1H), 6.19 (s, 1H), 7.22–7.26 (m, 2H), 7.32–7.42 (m, 3H).

[1116] Step 2: (5RS)-2-oxo-5-phenylpyrrolidin-l-aminium chloride

[1117]

[1118] 4.0M hydrogen chloride in dioxan (100 mL, 400 mmol) was added at room temperature to a solution of tert-butyl [(5RS)-2-oxo-5-phenylpyrrolidin-l-yl]carbamate (26.05 g, 94.27 mmol) in dioxane (100 mL). The resulting thick colourless suspension was stirred at rt overnight. The precipitate was then collected by filtration and washed with dioxane (25 mL) and air dried to provide the title compound as a colourless powdered solid (18.55 g, 93 %): 1H NMR (500 MHz, DMSO-d6, 25°C) δ 1.74–1.85 (m, 1H), 2.3–2.61 (m, >3H overlapping DMSO), 4.82 (t, J = 6.9 Hz, 1H), 7.29–7.37 (m, 3H), 7.37–7.44 (m, 2H), 8.69 (brs, 3H).

[1119] Step 3: ethyl (5RS)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate

[1120]

[1121] Ethyl 2-ethoxy-2-iminoacetate (27.3 g, 188.08 mmol) was added as solution in ethanol (10 mL) to a colourless solution of (5RS)-2-oxo-5-phenylpyrrolidin-l-aminium chloride (20 g, 94.04 mmol) in ethanol (250 mL). Within minutes, a colourless precipitate began to form. The suspension was warmed and stirred at 40°C for 4 hours after which LC-MS indicated complete consumption of (5RS)-2-oxo-5- phenylpyrrolidin-l-aminium chloride. The reaction mixture was then concentrated and co-concentrated from toluene (2 x 250 mL) to remove residual ethanol. To the obtained colourless syrup was added Phosphorus(V) oxychloride (75 mL, 805 mmol) and the resulting mixture was stirred at 110°C for one hour. The reaction was then quenched by slow and careful addition of the dark brown solution to vigorously stirring ice / water (500 mL). The mixture was extracted with dichloromethane (3 x 150 mL) and the combined organic layers were passed through a phase separator and concentrated to dryness under reduced pressure. Automated flash chromatography (Biotage select, Biotage Sfar silica HC D 200 g / 20 uM) of the residual dark brown oil using ethyl acetate in heptane (isocratic 3CV 50 %, gradient 20CV 50-100 %) followed by concentration of the appropriate fractions gave the racemic title compound as a pale brown solid (13.6 g, 56 %):TH NMR (500 MHz, CDCl3, 25°C) δ 1.41 (3H, t), 2.62–2.73 (1H, m), 2.99–3.09 (1H, m), 3.1–3.19 (1H, m), 3.19–3.29 (1H, m), 4.38–4.52 (2H, m), 5.48 (1H, dd), 7.06–7.12 (2H, m), 7.29–7.39 (3H, m).

[1122] Step 4: ethyl (5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate and ethyl (5S)-5- phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate

[1123]

[1124] ethyl (5RS)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (40.9 g, 159 mmol) was separated (Column: Chiralcel OJ; dimension: 250x50 mm; Particle size: 5 mM; Mobile phase: 8%ethanol / ammonia 100 / 20 mM in carbon dioxide; Flow: 320 mL / min) followed by concentration of appropriate fractions to provide ethyl (5 / ?)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (peak 1, 19.5 g, 95 %): 1H NMR (500 MHz, CDCl3, 25°C) δ 1.41 (3H, t), 2.62–2.72 (1H, m), 2.99–3.09 (1H, m), 3.09–3.29 (2H, m), 4.37–4.52 (2H, m), 5.48 (1H, dd), 7.06–7.12 (2H, m), 7.29–7.39 (3H, m). Chiral HPLC: 98.9% e.e.; and ethyl (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (peak 2, 19.0 g, 93%): 1H NMR (500 MHz, CDCI3, 25°C) δ 1.41 (3H, t), 2.63–2.73 (1H, m), 3–3.1 (1H, m), 3.1–3.19 (1H, m), 3.19–3.3 (1H, m), 4.38–4.52 (2H, m), 5.48 (1H, dd), 7.06–7.12 (2H, m), 7.3–7.4 (3H, m). Chiral HPLC: 99.5% e.e.

[1125] Step 5: (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (intermediate 1). To a solution of ethyl (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (19.0 g, 73.8 mmol) in tetrahydrofurane (450 mL) was added aq. 1 M lithium hydroxide (148 mL, 147.7 mmol) and the turbid dark mixture was stirred at room temperature overnight. The reaction mixture was then acidified by the addition of aq. 1.0 M hydrochloric acid (200 mL) and the bulk of tetrahydrofurane was removed under reduced pressure before extracting with ethyl acetate (3 x 200 mL). A tan precipitate formed, which was isolated by by filtration and afforded 12.5 g. The remaining organic layer was washed with water (100 mL) and brine (50 mL), then passed through a phase separator and concentrated to afford another 5.0 g of tan solid. The solids were combined as slurries in methanol and concentrated. The residue was sonicated in t-butyl methyl ether (250 mL) and left to stand overnight, then filtered, washed with t-butyl methyl ether (50 mL) and air-dried to afford the title compound as a tan solid (15.4 g, 91 %): 1H NMR (500 MHz, DMSO-d6, 25°C) δ 2.51–2.6 (1H, m), 2.93–3.03 (1H, m), 3.05–3.23 (2H, m), 5.54–5.6 (1H, m), 7.21–7.26 (2H, m), 7.38 (3H, dq), 13.16 (<1H, s). Chiral HPLC: 99.9% e.e. Optical rotation: -94°, 589 nm, 20°C, methanol, c 0.7.

[1126] Intermediate 2: (5 / ?)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1127]

[1128] To a solution of ethyl (5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (170 mg, 0.66 mmol, prepared as described in step 4 for intermediate 1) in THF (4 mL) aq. 1.0 M aqueous lithium hydroxide (1.32 mL, 1.32 mmol) was added. The turbid yellow solution was stirred at room temperature overnight, then acidified by the addition of aq. 1.0 M hydrochloric acid (2 mL) and extracted into ethyl acetate (5 mL). The organic layer was passed through a phase separator and concentrated and the residue was suspended in t-butyl methyl ether (5 mL) with sonication, filtered and air-dried to afford the title compound as a colorourless solid (107 mg, 71 %): 1H NMR (500 MHz, DMSO-dg, 25°C) δ 2.51–2.6 (1H, m), 2.93–3.03 (1H, m), 3.04–3.23 (2H, m), 5.57 (1H, dd), 7.21–7.26 (2H, m), 7.32–7.43 (3H, m), 13.14 (1H, s). Chiral HPLC: 99.9% e.e.Intermediate 3: (5S)- / V-[3-(4-bromophenyl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (CRO-RIPKli-95-1-002)

[1129]

[1130] To a stirred solution of intermediate 1 (0.78 g, 3.40 mmol) and 3-(4-bromophenyl)oxetane-3-amine hydrochloride (1.35 g, 5.10 mmol, CAS RN: 1349718-53-1) in N, N-diisopropylethylamine (1.78 mL, 10.2 mmol) at 0°C was added propane phosphonic acid

[1131] anhydride (4.33 g, 6.81 mmol, 50 % solution in ethyl acetate). The reaction mixture was

[1132] stirred at rt for 2 h before the reaction mixture was diluted with ethyl acetate (200 mL) and washed subsequently with water (2 x 75 mL) and brine (1 x 100 mL). The organic layer was then dried (sodium sulfate), filtered and concentrated. The residue was purified by flash C18 chromatography, elution gradient 0-60 % acetonitrile in water (0.05 % formic acid). Approprate fractions were concentrated to afford the title compound as a white solid (0.945 g, 63 %). 1H NMR (400 MHz, DMSO-dg, 23°C) δ 2.58 (1H, ddt), 3.01 (1H, ddd), 3.08–3.27 (2H, m), 4.70 (2H, dd), 4.95–5.01 (2H, m), 5.59 (1H, dd), 7.24–7.32 (2H, m), 7.34–7.46 (3H, m), 7.46–7.55 (2H, m), 7.55–7.64 (2H, m), 9.71 (1H, s).

[1133] Intermediate 4: (5S)-5-phenyl- / V-{3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1134]

[1135] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (186 mg, 0.23 mmol) was added to intermediate 3 (500 mg, 1.14 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (578 mg, 2.28 mmol) and potassium acetate (223 mg, 2.28 mmol) in 1,4-dioxane (8 mL). The resulting mixture was stirred at 90 °C for 15 hours under nitrogen. The reaction mixture was then allowed to cool to rt, diluted with dichloromethane (125 mL), washed successively with water (75 mL) and brine (75 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using methanol in dichloromethane (stepwise gradient elution, 0-4 %) followed by concentration of the appropriate fractions gave the title compound as brown solid (0.43 g, 78 %): 1H NMR (300 MHz, DMSO-dg, 23°C) δ 1.27 (12H, s), 2.56 (1H, ddd), 2.93–3.28 (3H, m), 4.69 (2H, dd), 4.98 (2H, dd), 5.57 (1H, dd), 7.23–7.29 (2H, m), 7.33–7.43 (3H, m), 7.51–7.56 (2H, m), 7.65–7.71 (2H, m), 9.68 (1H, s).

[1136] Intermediate 5: 3-[4-(5-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-aminium trifluoroacetate

[1137]

[1138] o

[1139] Step 1: 4-bromo-5-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-l,2,3-triazole

[1140]

[1141] 2-(Trimethylsilyl)ethoxymethyl chloride, stabilized, tech. (566 mg, 3.40 mmol) was added to 4-bromo-5- methyl-2H-l,2,3-triazole (500 mg, 3.09 mmol, CAS RN: 805315-83-7), sodium hydride (111 mg, 4.63 mmol) in tetrahydrofurane (5 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 4 hours, then quenched with water (5 mL). The obtained mixture was diluted with ethyl acetate (20 mL) and washed successively with water (3 x5 mL) and brine (1x5 mL), then dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography using acetonitrile in water (20-60 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (400 mg, 44 %, mixture of regioisomers).

[1142] Step 2: tert-butyl {3-[4-(5-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-1,2,3-triazol-4- yl)phenyl]oxetan-3-yl}carbamate

[1143]

[1144] o

[1145] Palladium-tetrakis(triphenylphosphine) (134 mg, 0.12 mmol) was added to caesium fluoride (265 mg, 1.75 mmol), 4-bromo-5-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazole (170 mg, 0.58 mmol, mixture of isomers) and tert-butyl {3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]oxetan-3-yl}carbamate (262 mg, 0.70 mmol, CAS RN 1279090-25-3) in water (0.6 mL) and dioxane (3 mL) at rt under nitrogen. The resulting mixture was stirred at 90 °C for 16 hours. The obtained reaction mixture was combined with 2 parallel reaction mixtures similarly prepared from 4-bromo-5- methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazole (2 times 50 mg, 0.34 mmol), then diluted with ethyl acetate (100 mL), washed successively with water (1 x 75 mL) and brine (1 x 75 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow gum (240 mg, 57 %, mixture of regioisomers).

[1146] Step 3: 3-[4-(5-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-aminium trifluoroacetate (intermediate 6). To a stirred solution of tert-butyl {3-[4-(5-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-1,2,3-triazol-4- yl)phenyl]oxetan-3-yl}carbamate (70 mg, 13 mmol) was added trifluoroacetic acid (1 mL), then stirred at rt for 16 h. The reaction mixture was then concentrated and used without further purification in the next step (example 78).Intermediate 6: 3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-aminium trifluoroacetate

[1147]

[1148] Step 1: tert-butyl {3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-yl}carbamate

[1149]

[1150] 1, T-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (52 mg, 0.06 mmol) was added to potassium carbonate (88 mg, 0.64 mmol), tert-butyl {3-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]oxetan-3-yl}carbamate (120 mg, 0.32 mmol, CAS RN 1279090-25-3) and 5- bromo-l,4-dimethyl-lH-l,2,3-triazole (67.5 mg, 0.38 mmol, CAS RN 1040275-55-5) in 1,4-dioxane (1.5mL) and water (0.5 ml) under nitrogen. The resulting mixture was stirred at 90 °C for 2 hours, then filtered through celite and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.05 % formic acid (20-50 %). Concentration of the appropriate fractions gave the title compound as a white solid (100 mg, 91 %):TH NMR (500 MHz, DMSO) δ 1.41 (9H, s), 2.24 (3H, s), 3.95 (3H, s), 4.71 (2H, d), 4.86 (2H, d), 7.54–7.57 (2H, m), 7.64–7.67 (2H, m), 8.17 (1H, s).

[1151] Step 2: 3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-aminium trifluoroacetate (intermediate 6)

[1152] Trifluoroacetic acid (1.0 mL, 13 mmol) was added to tert-butyl {3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5- yl)phenyl]oxetan-3-yl}carbamate (82 mg, 0.24 mmol) in DCM (3.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours, then concentrated to afford the title compound which was used in the next step without further purification (65 mg, 80 %): 1H NMR (500 MHz, DMSO) δ 2.25 (3H, s), 3.96 (3H, s), 4.99 (4H, t), 7.67 (2H, d), 7.72 (2H, d), 9.09 (2H, s).

[1153] Intermediate 7: 3-[4-(5-methyl-lH-l,2,3-triazol-l-yl)phenyl]oxetan-3-aminium chloride

[1154]

[1155] o

[1156] Step 1: 2-methyl- / V-{3-[4-(5-methyl-lH-l,2,3-triazol-l-yl)phenyl]oxetan-3-yl}propane-2-sulfinamide

[1157]

[1158] n-Butyllithium (1.68 mL, 4.20 mmol) was added dropwise to l-(4-bromophenyl)-5-methyl-lH-l,2,3- triazole (1 g, 4.20 mmol, CAS RN 20177-64-4) in tetrahydrofurane (15 mL) at -78°C over a period of 2minutes under nitrogen, stirred for 10 min, then added 2-methyl- / V-(oxetan-3-ylidene)propane-2-sulfinamide (0.736 g, 4.20 mmol, CAS RN 1158098-73-7) in tetrahydrofurane (3 mL) dropwise at -78°C and stirred for 1 hour. Then the reaction mixture was allowed to warm to rt and stirred for another 1 hour. The reaction mixture was then poured into ice water, extracted with ethyl acetate (3 x 100 mL) and the organic layer was dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using methanol in dichloromethane (0-10 %) followed by concentration of the appropriate fractions gave the title compound as an yellow oil (0.87 g, 62 %):1H NMR (400 MHz, DMSO-dg, 22°C) δ 1.14 (9H, s), 2.3–2.39 (3H, m), 4.78 (1H, d), 4.95 (1H, d), 5.01 (1H, d), 5.05 (1H, d), 6.45 (1H, s), 7.63–7.68 (2H, m), 7.69–7.72 (1H, m), 7.72–7.77 (2H, m).

[1159] Step 2: 3-[4-(5-methyl-lH-l,2,3-triazol-l-yl)phenyl]oxetan-3-aminium chloride (intermediate 7).

[1160] 4 M HCI in dioxane (0.15 mL, 0.60 mmol) was added to 2-methyl- / V-{3-[4-(5-methyl-lH-l,2,3-triazol-l-yl)phenyl]oxetan-3-yl}propane-2-sulfinamide (100 mg, 0.30 mmol) in dichloromethane (3 mL) at 0°C, then stirred for 1 h. The obtained precipitate was collected by filtration, washed with diethyl ether, and dried in vacuum to afford the title compound which was used in the next step without further purification (70 mg, 88 %, 20 % ring opened product):1H NMR (300 MHz, DMSO, 24°C) δ 2.37 (3H, d), 4.94 (2H, d), 5.11 (2H, d), 7.74 (2H, q), 7.76 (1H, d), 7.83–7.95 (2H, m), 9.60 (3H, s).

[1161] Intermediate 9: 3-[4-(l-methyl-4-nitro-lH-pyrazol-5-yl)phenyl]oxetan-3-amine

[1162]

[1163] Palladium^ I) acetate (177 mg, 0.79 mmol) and Butyldi-l-adamantylphosphine (423 mg, 1.18 mmol) were added to pivalic acid (121 mg, 1.18 mmol), potassium carbonate (1631 mg, 11.80 mmol), 1-Methyl-4-nitro-lH-pyrazole (500mg, 3.93 mmol, CAS RN 3994-50-1) and 3-(4-bromophenyl)oxetan-3-amine (897 mg, 3.93 mmol, CAS RN 1349972-68-4) in dioxane (10 mL) at rt under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours, then allowed to cool to rt, filtered through celite and concentrated. Flah chromatography of the residue using methanol in dichloromethane (0-9 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (1000 mg, 93 %, 86 % purity):XH NMR (500 MHz, DMSO-d6) δ 2.88 (2H, s), 3.72 (3H, s), 4.71 (2H, d), 4.77 (2H, d), 7.58–7.63 (2H, m), 7.77–7.81 (2H, m), 8.39 (1H, s).

[1164] Intermediate 10. (5S)-5-phenyl- / V-(3-{4-[l-(piperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1165]

[1166] Prepared similar as described in example 41 from intermediate 3 (100 mg, 0.23 mmol) and 4-[4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine (63 mg, 0.23 mmol, CAS RN 1175708-03-8). Flash C-18 chromatography of the residue using acetonitrile in water with 0.1% formic acid (30-40 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (80 mg, 69 %, 90 % purity):1H NMR (500 MHz, DMSO-d6) δ 1.07 (4H, s), 2.01–2.12 (2H, m), 2.14 (1H, s), 2.17 (1H, d), 2.57 (1H, ddt), 2.89–2.98 (2H, m), 2.98–3.06 (1H, m), 3.08–3.15 (1H, m), 3.17 (3H, s), 3.22 (2H, ddd), 3.30 (2H, d), 3.84–3.97 (1H, m), 4.42 (1H, p), 4.74 (2H, dd), 4.99 (2H, dd), 5.58 (1H, dd), 7.24–7.3 (2H, m), 7.3–7.44 (4H, m), 7.49 (2H, dd), 7.53–7.61 (2H, m), 7.90 (1H, s), 8.20 (1H, s), 8.38 (1H, s), 9.65 (1H, s).

[1167] Intermediate 11. 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]pyrimidin-2-amine

[1168]

[1169] Step 1: tert-butyl [l-(5-iodofuran-2-yl)cyclopropyl]carbamate

[1170]

[1171] / V-lodosuccinimide (202 mg, 0.90 mmol) was added to tert-butyl [l-(furan-2-yl)cyclopropyl]carbamate (200 mg, 0.90 mmol, CAS RN 1159734-58-3) in DMF (4 mL) under nitrogen. The resulting mixture was stirred at 25 °C for 2 h then poured in aq. 10 % sodium thiosulphate (50 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a brown solid (181 mg, 58 %):TH NMR (300 MHz, CDCl3, 24°C) δ 1.21 (s, 2H), 1.31 (s, 2H), 1.46 (s, 9H), 6.08 (d, J = 3.2 Hz, 1H), 6.44 (d, J = 3.2 Hz, 1H).

[1172] Step 2: tert-butyl {l-[5-(2-aminopyrimidin-5-yl)furan-2-yl]cyclopropyl}carbamate

[1173]

[1174] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (150 mg, 0.18 mmol) was added to potassium phosphate, tribasic (973 mg, 4.58 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (658 mg, 2.98 mmol, CAS RN 402960-38-7) and tert-butyl [l-(5-iodofuran-2-yl)cyclopropyl]carbamate (800 mg, 2.29 mmol) in 1,4-dioxane (10 mL) and water (3.3 mL) at25°C under nitrogen. The resulting mixture was stirred at 80 °C for 12 hours. The reaction mixture was allowed to reach rt, then poured into water (100 mL) and extracted with ethyl acetate (3 x 25 ml), dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.05 % formic acid (0-80 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (380 mg, 52 %):1H NMR (300 MHz, DMSO-dg, 26°C) δ 0.98–1.12 (2H, m), 1.22 (2H, s), 1.39 (9H, s), 6.10 (1H, s), 6.64 (1H, d), 6.83 (2H, s), 7.70 (1H, s), 8.49 (2H, s).

[1175] Step 3: tert-butyl {l-[6-(2-aminopyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}carbamate

[1176] H r r

[1177] ■NX^N-N

[1178]

[1179] / V-bromosuccinimide (309 mg, 1.74 mmol) was added to tert-butyl {l-[5-(2-aminopyrimidin-5-yl)furan-2- yl]cyclopropyl}carbamate (500mg, 1.58 mmol) in THF (4.5 mL) and water (0.5 mL) at -20 °C under nitrogen followed by addition of hydrazine hydrate (727 mg, 14.22 mmol). The resulting mixture was stirred at -15 °C for 30 min. The solvent was then removed under reduced pressure. Flash C-18 chromatography of the residue using acetonitrile in water with 0.05 % formic acid (0-60 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (200 mg, 38.5 %):1H NMR (300 MHz, DMSO, 23°C) δ 1.1–1.28 (4H, m), 1.41 (10H, d), 7.10 (2H, s), 7.92 (1H, s), 8.09 (1H, d), 8.95 (2H, s).

[1180] Step 4: 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]pyrimidin-2-amine (intermediate 11)

[1181] Hydrochloric acid in dioxane (0.111 mL, 3.65 mmol) was added to tert-butyl {l-[6-(2-aminopyrimidin-5- yl)pyridazin-3-yl]cyclopropyl}carbamate (120 mg, 0.37 mmol) in dioxane (5 mL) at 25°C under nitrogen. The resulting mixture was stirred at 25 °C for 2 h, then neutralized using aq. saturated sodium carbonate and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 10 N ammonium bicarbonate (0-60 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (75 mg, 90 %).

[1182] Intermediate 12. 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methylpyrimidin-2-amine

[1183]

[1184] Step 1: 3-(l-azidocyclopropyl)-6-chloropyridazine

[1185]

[1186] Diphenylphosphonic azide (457 mg, 1.66 mmol) was added to triethylamine (168 mg, 1.66 mmol) and 1- (6-chloropyridazin-3-yl)cyclopropane-l-carboxylic acid (300 mg, 1.51 mmol, CAS RN 1510730-43-4) in dichloromethane (20 mL) at rt under nitrogen. The resulting mixture was stirred at 40 °C for 2 hours. The reaction mixture was then diluted with dichloromethane (50 mL), washed successively with aq. saturated sodium hydrogen carbonate (2 x 50 mL) and water (2 x 50 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (240 mg, 71.1 %): 1H NMR (400 MHz, DMSO-d6, 23°C) δ 1.68–1.79 (4H, m), 7.94 (1H, d), 8.04 (1H, d).

[1187] Step 2: benzyl [l-(6-chloropyridazin-3-yl)cyclopropyl]carbamate

[1188]

[1189] -°YN)A'N

[1190] Benzylalcohol (5 mL, 46.24 mmol) was added to triethylamine (110 mg, 1.08 mmol) and 3-(l- azidocyclopropyl)-6-chloropyridazine (220 mg, 0.98 mmol) in toluene (20 mL) at rt under nitrogen. The resulting mixture was stirred at 90 °C for 2 hours, then concentrated. Flash C18 chromatography of the residue using acetonitrile in water with 0.1 % ammonia (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (280 mg, 94 %):1H NMR (300 MHz, DMSO-dg, 22°C) δ 1.31 (2H, q), 1.58 (2H, q), 5.04 (2H, s), 7.22–7.41 (5H, m), 7.63 (1H, d), 7.81 (1H, d), 8.36 (1H, s).

[1191] Step 3: benzyl {l-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}carbamate

[1192]

[1193] V / v

[1194] Tetrakis(triphenylphosphine)palladium(0) (107 mg, 0.09 mmol) was added to potassium carbonate (319 mg, 2.30 mmol), benzyl [l-(6-chloropyridazin-3-yl)cyclopropyl]carbamate (280 mg, 0.92 mmol) and 4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (217 mg, 0.92 mmol, CAS RN 944401-55-2) in 1,4-dioxane (15 mL) and water (5 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 3 hours, then concentrated. Flash C18 chromatography of the residue using acetonitrile in water with 0.1 % ammonia (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (240 mg, 69 %):XH NMR (400 MHz, DMSO-d6, 22°C) δ 1.32 (2H, q), 1.64 (2H, q), 2.37 (3H, s), 5.07 (2H, s), 6.90 (2H, s), 7.18–7.5 (5H, m), 7.59 (1H, d), 7.80 (1H, d), 8.35 (2H, d).

[1195] Step 4: 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methylpyrimidin-2-amine (intermediate 12) Hydrobromic acid (2 mL, 36.83 mmol) was added to benzyl {l-[6-(2-amino-4-methylpyrimidin-5- yl)pyridazin-3-yl]cyclopropyl}carbamate (200 mg, 0.53 mmol) in dichloromethane (5 mL) under nitrogen. The resulting mixture was stirred at rt for 3 h, then concentrated. Flash C18 chromatography of theresidue using acetonitrile in water with 0.1 % ammonia (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (55 mg, 43 %):1H NMR (400 MHz, DMSO-d6, 22°C) 6 1.11 (2H, q), 1.38 (2H, q), 2.36 (3H, s), 3.61-4.21 (2H, q), 6.87 (2H, s), 7.81 (1H, d), 8.01 (1H, d), 8.32 (1H, s).

[1196] Intermediate 13. 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methylpyridin-2-amine

[1197]

[1198] Step 1: benzyl {l-[6-(6-amino-4-methylpyridin-3-yl)pyridazin-3-yl]cyclopropyl}carbamate

[1199]

[1200] [l,l'-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (48 mg, 0.07 mmol) was added to 4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine

[1201] (154 mg, 0.66 mmol, CAS RN 1220219-94-2), benzyl [l-(6-chloropyridazin-3-yl)cyclopropyl]carbamate (100 mg, 0.33 mmol, prepared as described in step 2, intermediate 12) and potassium carbonate (91 mg, 0.66 mmol) in dioxane (3 mL) and water (1 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours. The reaction mixture was allowed to cool to rt, diluted with EtOAc (10 mL), washed successively with water (2 x 5 mL), brine (2 x 5 mL), then dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-100 %) followed by concentration of the appropriate fraction gave the title compound a brown solid (100 mg, 81 %):1H NMR (300 MHz, DMSO-d6) 6 1.29 (2H, d), 1.64 (1H, q), 2.27 (3H, d), 5.08 (1H, s), 6.27 (2H, d), 7.40 (3H, d), 7.57 (1H, d), 7.74 (1H, d), 7.99 (1H, s), 8.36 (1H, s).

[1202] Step 2: 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methylpyridin-2-amine (intermediate 13)

[1203] Benzyl {l-[6-(6-amino-4-methylpyridin-3-yl)pyridazin-3-yl]cyclopropyl}carbamate (80 mg, 0.21 mmol) was added to l-(Trimethylsilyl)lmidazole (149 mg, 1.07 mmol) in dichloromethane (5 mL) under nitrogen. The resulting mixture was stirred at 40 °C for 2 hours, then concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-10 %) followed by concentration of the appropriate fraction gave the title compound a yellow solid (50 mg, 97 %, 80 % purity):1H NMR (400 MHz, DMSO-dg, 23°C) 6 1.95–2.47 (1H, m), 7.47–8.28 (2H, m), 8.97 (1H, s).

[1204] Intermediate 14. 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methoxypyrimidin-2-amine

[1205]

[1206] Step 1: benzyl {l-[6-(2-amino-4-methoxypyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}carbamate

[1207]

[1208] Prepared similar as described in step 3 for intermediate 12 from benzyl [l-(6-chloropyridazin-3-yl)cyclopropyl]carbamate (170 mg, 0.56 mmol, prepared as described in step 2, intermediate 12) and 4-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (703 mg, 2.8 mmol, CAS RN 944401-63-2). Yellow solid (80 mg, 36 %):1H NMR (500 MHz, DMSO-d6) 6 1.25–1.31 (2H, m), 1.61 (2H, q), 3.93 (3H, s), 5.07 (2H, s), 7.02 (2H, s), 7.22–7.43 (5H, m), 7.54 (1H, d), 7.91 (1H, d), 8.34 (1H, s), 8.63 (1H, s).

[1209] Step 2: 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methoxypyrimidin-2-amine (intermediate 14) Iodotrimethylsilane (178 mg, 0.89 mmol) was added to benzyl {l-[6-(2-amino-4-methoxypyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}carbamate (70 mg, 0.18 mmol) in dichloromethane (2 mL). The resulting mixture was stirred at RT for 2 hours. The reaction mixture was quenched with methanol (0.5 mL) and pH was adjusted to 8 with sodium hydrogen carbonate(s), filtered and concentrated. Flash C18 chromatography of the residue using acetonitrile in water (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a brown solid (30 mg, 65 %): 1H NMR (300 MHz, DMSO-dg, 21°C) 6 1.06 (2H, q), 1.34 (2H, q), 3.91 (3H, s), 6.98 (2H, s), 7.86–7.95 (2H, m), 8.61 (1H, s).

[1210] Intermediate 15. 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methoxypyridin-2-amine

[1211]

[1212] Step 1: benzyl {l-[6-(6-amino-4-methoxypyridin-3-yl)pyridazin-3-yl]cyclopropyl}carbamate

[1213]

[1214] Prepared similar as described in step 1 for intermediate 13 from benzyl [l-(6-chloropyridazin-3-yl)cyclopropyl]carbamate (0.405 g, 1.33 mmol, prepared as described in step 2, intermediate 12) and 4-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.0 g, 4 mmol, CAS RN 1333220-57-7). Yellow solid (0.110 g, 21 %): 1H NMR (300 MHz, DMSO-d6, 23°C) 6 1.35 (2H, d), 1.56–1.73 (2H, m), 3.97 (3H, s), 5.07 (1H, s), 6.53 (1H, s), 7.23-7.44 (5H, m), 7.64 (1H, d), 7.88–8.13 (3H, m), 8.36 (2H, d).

[1215] Step 2: 5-[6-(l-aminocyclopropyl)pyridazin-3-yl]-4-methoxypyridin-2-amine (intermediate 15)Prepared similar as described in step 2 of intermediate 14 from benzyl {l-[6-(6-amino-4-methoxypyridin-3-yl)pyridazin-3-yl]cyclopropyl}carbamate (0.100 g, 0.26 mmol). White solid (0.017 g, 26 %).

[1216] Intermediate 16. 5-[5-(l-aminocyclopropyl)pyridin-2-yl]pyrimidin-2-amine

[1217]

[1218] Step 1: tert-butyl [l-(6-bromopyridin-3-yl)cyclopropyl]carbamate

[1219]

[1220] Triethylamine (1140 mg, 11.26 mmol) was added to di-tert-butyl dicarbonate (983 mg, 4.51 mmol) and l-(6-bromopyridin-3-yl)cyclopropan-l-amine (800 mg, 3.75 mmol, CAS RN 1060811-36-0) in dichloromethane (20 mL) under nitrogen. The resulting mixture was stirred at 40 °C for 3 hours, then concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.1 % ammonia (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (900 mg, 77 %): 1H NMR (300 MHz, DMSO) 6 1.17 (4H, dt), 1.37 (9H, s), 7.44 (1H, ddd), 7.55 (1H, d), 7.80 (1H, s), 8.13–8.19 (1H, m).

[1221] Step 2: tert-butyl {l-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]cyclopropyl}carbamate

[1222]

[1223] Prepared similarly as described for step 1, intermediate 13 from tert-butyl [l-(6-bromopyridin-3-yl)cyclopropyl]carbamate (0.380 g, 1.21 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.322 g, 1.46 mmol, CAS RN 402960-38-7). Yellow solid (0.200 g, 50 %).

[1224] Step 3: 5-[5-(l-aminocyclopropyl)pyridin-2-yl]pyrimidin-2-amine (intermediate 16)

[1225] tert-butyl {l-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]cyclopropyl}carbamate (0.256 g, 0.7 mmol) in dioxane (5 mL) was treated with HCI in dioxane (0.21 mL, 7 mmol) at rt for 3 h, then neutralized using aq. saturated sodium hydrogen carbonate, filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (0.15 g, 94 %):1H NMR (400 MHz, DMSO, 24°C) 6 1.27–1.35 (m, 2H), 1.45–1.57 (m, 2H), 8.11 (d, J = 2.4 Hz, 2H), 8.77 (t, J = 1.5 Hz, 1H), 9.23 (s, 2H), 9.33 (s, 2H).

[1226] Intermediate 17. 5-[6-(l-aminocyclopropyl)pyridin-3-yl]pyrimidin-2-amine

[1227]

[1228] Step 1: tert-butyl {l-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]cyclopropyl}carbamate

[1229]

[1230] Prepared similar as described in step 2, intermediate 11 from tert-butyl [l-(5-bromopyridin-2-yl)cyclopropyl]carbamate (0.35 g, 1.12 mmol, CAS RN 828911-20-2), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.322 g, 1.46 mmol, CAS RN 402960-38-7). Yellow solid (0.17 g, 46 %

[1231]

[1232] ): NMR (400 MHz, DMSO, 24°C) 6 1.12–1.17 (2H, m), 1.26 (2H, d), 1.43 (9H, s), 6.84 (2H, s), 7.34–7.39 (1H, m), 7.81 (1H, s), 7.94–8.01 (1H, m), 8.59 (2H, s), 8.68 (1H, d).

[1233] Step 2: 5-[6-(l-aminocyclopropyl)pyridin-3-yl]pyrimidin-2-amine (intermediate 17)

[1234] Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]cyclopropyl}carbamate (0.15 g, 0.46 mmol). White solid (0.090 g, 86 %):1H NMR (400 MHz, DMSO, 24°C) 6 1.38–1.45 (2H, m), 1.47–1.54 (2H, m), 6.91 (2H, s), 7.41 (1H, dd), 8.10 (1H, dd), 8.66 (2H, s), 8.82 (1H, dd).

[1235] Intermediate 18. l-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropan-l-aminium chloride

[1236]

[1237] Step 1: tert-butyl {l-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropyl}carbamate

[1238]

[1239] Prepared similar as described for step 1, intermediate 13 from tert-butyl [l-(5-bromopyridin-2-yl)cyclopropyl]carbamate (120 mg, 0.38 mmol, CAS RN 828911-20-2) and 4-methyl-5-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (135 mg, 0.57 mmol, CAS RN 944401-55-2). Yellow solid (80 mg, 61 %):XH NMR (400 MHz, DMSO, 24°C) 6 1.18 (1H, d), 1.25 (3H, d), 1.38–1.48 (9H, m), 2.35 (3H, s), 7.42 (1H, d), 7.82 (2H, d), 8.32 (1H, s), 8.46 (1H, d).

[1240] l-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropan-l-aminium chloride (intermediate 19) Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropyl}carbamate (75 mg, 0.22 mmol). The product obtained after concentration of the reaction mixture (yellow oil) was used as such without further purification in the next step.Intermediate 19. l-[5-(3-methyl-lH-pyrazol-4-yl)pyridin-2-yl]cyclopropan-l-aminium chloride

[1241]

[1242] Step 1: tert-butyl {l-[5-(3-methyl-lH-pyrazol-4-yl)pyridin-2-yl]cyclopropyl}carbamate

[1243]

[1244] Prepared similar as described for step 1, intermediate 13 from from tert-butyl [l-(5-bromopyridin-2- yl)cyclopropyl]carbamate (100 mg, 0.32 mmol, CAS RN 828911-20-2) and 3-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (73 mg, 0.35 mmol, CAS RN 936250-20-3). Yellow solid (55 mg, 55 %):TH NMR (300 MHz, DMSO, 23°C) 6 1.11 (2H, q), 1.2–1.39 (2H, m), 1.43 (9H, s), 2.37 (3H, d), 7.34 (1H, d), 7.6–7.95 (3H, m), 8.42–8.62 (1H, m), 12.54 (1H, s).

[1245] Step 2: l-[5-(3-methyl-lH-pyrazol-4-yl)pyridin-2-yl]cyclopropan-l-aminium chloride (intermediate 19) Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[5-(3-methyl-lH-pyrazol-4- yl)pyridin-2-yl]cyclopropyl}carbamate (50 mg, 0.16 mmol). The product obtained after concentration of the reaction mixture (yellow oil) was used as such without further purification in the next step.

[1246] Intermediate 20. l-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3-yl]cyclopropan-l-aminium chloride

[1247]

[1248] Step 1: tert-butyl {l-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3-yl]cyclopropyl}carbamate

[1249] h\ ii T

[1250]

[1251] T A

[1252] Prepared similar as described for step 1, intermediate 13 from tert-butyl [l-(6-bromopyridin-3- yl)cyclopropyl]carbamate (300 mg, 0.96 mmol, prepared as described in step 1, intermediate 16) and 4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (225 mg, 0.96 mmol, CAS RN 944401-55-2). Yellow solid (160 mg, 49 %):TH NMR (300 MHz, DMSO, 23°C) 6 1.19 (4H, dd), 1.40 (9H, s), 2.37 (3H, s), 6.73 (2H, s), 7.43–7.56 (2H, m), 7.82 (1H, s), 8.27 (1H, s), 8.42 (1H, d).

[1253] Step 2: l-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3-yl]cyclopropan-l-aminium chloride (intermediate 20).

[1254] Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[6-(2-amino-4- methylpyrimidin-5-yl)pyridin-3-yl]cyclopropyl}carbamate (150 mg, 0.44 mmol). The product obtainedafter concentration of the reaction mixture (yellow oil) was used as such without further purification in the next step.

[1255] Intermediate 21. l-[6-(3-methyl-lH-pyrazol-4-yl)pyridin-3-yl]cyclopropan-l-aminium chloride

[1256]

[1257] Step 1: tert-butyl {l-[6-(3-methyl-lH-pyrazol-4-yl)pyridin-3-yl]cyclopropyl}carbamate

[1258]

[1259] T A

[1260] Prepared similar as described for step 1, intermediate 13 from tert-butyl [l-(6-bromopyridin-3- yl)cyclopropyl]carbamate (300 mg, 0.96 mmol, prepared as described in step 1, intermediate 16) and 3- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (219 mg, 1.05 mmol, CAS RN 936250-20-3). Yellow solid (95 mg, 32 %):TH NMR (300 MHz, DMSO, 23°C) 6 1.15 (4H, dt), 1.39 (9H, s), 2.39 (3H, s), 7.33–7.58 (3H, m), 7.77 (1H, s), 8.34 (1H, d), 12.66 (1H, d).

[1261] Step 2: l-[6-(3-methyl-lH-pyrazol-4-yl)pyridin-3-yl]cyclopropan-l-aminium chloride (intermediate 21)

[1262] Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[6-(3-methyl-lH-pyrazol-4- yl)pyridin-3-yl]cyclopropyl}carbamate (85 mg, 0.27 mmol). The product obtained after concentration of the reaction mixture (yellow oil) was used as such without further purification in the next step.

[1263] Intermediate 22. l-[5-(2-aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropan-l-aminium formate

[1264]

[1265] Step 1: tert-butyl [l-(5-bromopyrazin-2-yl)cyclopropyl]carbamate

[1266]

[1267] Titanium isopropoxide (340 mg, 1.20 mmol) was added to 5-bromopyrazine-2-carbonitrile (200 mg, 1.09 mmol) in diethyl ether (10 mL) at 0°C. After 5 min ethylmagnesium bromide (319 mg, 2.39 mmol) was added and the resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was cooled to 0 °C and 1 M boron trifluoride etherate in diethyl ether (2.174 mL, 2.17 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h, then quenched with water and basified with aq. saturated sodium carbonate, diluted with water (75 mL). The mixture was extracted with ethyl acetate (3 x 15 mL) and the combined organic layers were dried (sodium sulphate), filtered and concentrated to obtain a red oil (400 mg). The residue was dissolved in tetrahydrofurane (10 mL) and triethyl amine (0.52 mL, 3.74 mmol), cooled to 0 °C and added di-tert-butyl dicarbonate (408 mg, 1.87 mmol). The reaction mixture wasstirred at rt for 2 h, then diluted with water (50 mL), extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated which gave the crude title compound as a yellow oil.

[1268] Step 2: tert-butyl {l-[5-(2-aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropyl}carbamate

[1269]

[1270] Prepared similar as described in step 1 of intermediate 13 from tert-butyl [l-(5-bromopyrazin-2- yl)cyclopropyl]carbamate (70 mg, 0.22 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-amine (74 mg, 0.33 mmol, CAS RN 402960-38-7). Yellow oil (54 mg, 74 %):1H-NMR (400 MHz, DMSO, 24°C) 6 1.16–1.31 (m, 4H), 1.44 (s, 9H), 7.08 (s, 2H), 7.91 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.51 (s, 1H), 8.92 (s, 2H).

[1271] Step 3: l-[5-(2-aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropan-l-aminium formate (intermediate 22). Hydrochloric acid in ethyl acetate (0.083 mL, 2.74 mmol) was added to tert-butyl {l-[5-(2- aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropyl}carbamate (45 mg, 0.14 mmol) in 1,4-dioxane (5 mL) at 23°C under nitrogen. The resulting mixture was stirred at 25 °C for 4 hours, then concentrated. Flash C18 chromatography of the residue using acetonitrile in water with 0.5 % formic acid (0-80 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (24 mg) which was used in the next step.

[1272] Intermediate 23. l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropan-l-aminium trifluoroacetate

[1273] Step 1: tert-butyl [l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropyl]carbamate

[1274]

[1275] '°YN2?

[1276] Prepared similar as described in step 1 of intermediate 13 from tert-butyl [l-(5-bromopyrimidin-2- yl)cyclopropyl]carbamate (100 mg, 0.32 mmol, CAS RN 827628-33-1) and 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-amine (141 mg, 0.64 mmol, CAS RN 402960-38-7). Yellow solid (90 mg, 86 %):TH NMR (300 MHz, DMSO, 24°C) 6 1.22 (4H, dd), 1.44 (9H, d), 7.20 (2H, d), 7.59 (1H, s), 8.70 (2H, s), 8.76 (1H, s), 9.15 (1H, s).

[1277] Step 2: l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropan-l-aminium trifluoroacetate (intermediate 23)To a solution of tert-butyl [l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropyl]carbamate (80 mg, 0.24 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL), then stirred at rt for 1 h. The reaction mixture was then concentrated and used directly in the next step without further purification.

[1278] Intermediate 24. 2'-(l-aminocyclopropyl)-4-methyl[5,5'-bipyrimidin]-2-amine

[1279] p

[1280] Step 1: tert-butyl [l-(2'-amino-4'-methyl[5,5'-bipyrimidin]-2-yl)cyclopropyl]carbamate

[1281] r T

[1282] h1

[1283]

[1284] Prepared similar as described in step 1 of intermediate 13 from tert-butyl [l-(5-bromopyrimidin-2- yl)cyclopropyl]carbamate (100 mg, 0.32 mmol, CAS RN 827628-33-1) and 4-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (150 mg, 0.64 mmol, CAS RN 944401-55-2). This was combined with a smaller batch from tert-butyl [l-(5-bromopyrimidin-2-yl)cyclopropyl]carbamate (10 mg, 0.03 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (15 mg, 0.06 mmol). Yellow solid (120 mg, residual solvent):TH NMR (300 MHz, DMSO, 24°C) 6 1.2–1.29 (4H, m), 1.37–1.51 (9H, m), 7.31–7.51 (2H, m), 7.60 (1H, s), 8.29 (1H, s), 8.74 (2H, s).

[1285] Step 2: 2'-(l-aminocyclopropyl)-4-methyl[5,5'-bipyrimidin]-2-arriine (intermediate 24)

[1286] Prepared similar as described in step 2 for intermediate 23 from tert-butyl [l-(2'-amino-4'-methyl[5,5'- bipyrimidin]-2-yl)cyclopropyl]carbamate (110 mg, 0.32 mmol). Flash C18 chromatography using acetonitrile in water with 5 % ammonium bicarbonate (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (80 mg, quantitative).

[1287] Intermediate 25. l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropan-l-aminium chloride

[1288]

[1289] Step 1: tert-butyl [l-(2-chloropyrimidin-5-yl)cyclopropyl]carbamate

[1290]

[1291] To a stirred mixture of 5-bromo-2-chloropyrimidine (420 mg, 2.17 mmol), tert-butyl (l-{[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)oxy]carbonyl}cyclopropyl)carbamate(827 mg, 2.39 mmol, CAS RN 2240185-66-2), zinc (1420 mg, 21.71 mmol), Nickel chloride, dimethoxyethane adduct (95 mg, 0.43 mmol), 5-methoxypicolinimidamide hydrochloride (81 mg, 0.43 mmol) and tetrabutylammonium iodide (802 mg, 2.17 mmol) in dimethyl acetamide (5 mL) at was added trifluoroacetic acid (0.084 mL, 1.09 mmol) in dimethylacetamide (0.5 mL), then stirred a rt for 2 h. The reaction mixture was then quenched with water (10 mL), extracted with ethyl acetate (3 x 25 mL) and the combined oraganic layers were dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-70 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (240 mg, 41 %):1H NMR (500 MHz, DMSO) 6 1.18–1.21 (2H, m), 1.31 (2H, d), 1.38 (9H, s), 7.87 (1H, s), 8.51 (2H, s).

[1292] Step 2: tert-butyl [l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropyl]carbamate

[1293]

[1294] Prepared similar as described in step 1, intermediate 13 using 1,1'- Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (36 mg, 0.04 mmol) from tert-butyl [l-(2-chloropyrimidin-5-yl)cyclopropyl]carbamate (120 mg, 0.44 mmol) and 5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (98 mg, 0.44 mmol, CAS RN 402960-38-7). White solid (80 mg, 55 %):XH NMR (500 MHz, DMSO) 6 1.16–1.2 (2H, m), 1.29 (2H, q), 1.39 (9H, s), 7.19 (2H, s), 7.86 (1H, s), 8.57 (2H, d), 9.08 (2H, s).

[1295] Step 3: l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropan-l-arninium chloride (intermediate 25)

[1296] tert-butyl [l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropyl]carbamate (50 mg, 0.15 mmol) was stirred with 4 M hydrochloric acid in dioxane (1.2 mL) for 30 min, then concentrated and used directly in the next step without further purification.

[1297] Intermediate 26. l-[4-(2-aminopyrimidin-5-yl)-3-methylphenyl]cyclopropan-l-aminium chloride

[1298]

[1299] Step 1: tert-butyl [l-(4-bromo-3-methylphenyl)cyclopropyl]carbamate

[1300]

[1301] Prepared similar as described for step 1, intermediate 22 from 4-bromo-3-methylbenzonitrile (1 g, 5.1 mmol). White solid (0.35 g, 21 %):1H NMR (400 MHz, DMSO, 21°C) 6 1.10 (4H, s), 1.37 (9H, s), 2.30 (3H, s), 6.90 (1H, d), 7.06 (1H, d), 7.45 (1H, d), 7.71 (1H, s).Step 2: tert-butyl {l-[4-(2-aminopyrimidin-5-yl)-3-methylphenyl]cyclopropyl}carbamate

[1302]

[1303] Prepared similar as described in step 1, intermediate 13 using 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (73 mg, 0.09 mmol) from tert-butyl [l-(4-bromo-3-methylphenyl)cyclopropyl]carbamate (290 mg, 0.89 mmol) and 5-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (197 mg, 0.89 mmol, CAS RN 402960-38-7). White solid (250 mg, 83 %):TH NMR (500 MHz, DMSO) 6 1.12 (4H, s), 1.39 (9H, s), 2.23 (3H, s), 6.68 (2H, s), 7.02 (2H, d), 7.11 (1H, d), 7.70 (1H, s), 8.23 (2H, s).

[1304] Step 3: l-[4-(2-aminopyrimidin-5-yl)-3-methylphenyl]cyclopropan-l-aminium chloride (intermediate 26)

[1305] Prepared similar as described in step 3, intermediate 25 and used in the next step without further purification. White solid (32 mg, 79 %):TH NMR (500 MHz, DMSO) 6 1.33 (2H, d), 1.44–1.48 (2H, m), 2.44 (3H, s), 7.48 (1H, s), 7.91 (1H, s), 8.63 (3H, d), 9.03 (2H, s).

[1306] Intermediate 27: l-[4-(2-aminopyrimidin-5-yl)-2-methylphenyl]cyclopropan-l-aminium chloride

[1307]

[1308] Step 1: tert-butyl [l-(4-bromo-2-methylphenyl)cyclopropyl]carbamate

[1309]

[1310] Prepared similar as described for step 1, intermediate 22 from 4-bromo-2-methylbenzonitrile (1 g, 5.1 mmol). White solid (0.60 g, 36 %):XH NMR (400 MHz, DMSO, 21°C) 60.91 (2H, d), 0.99–1.04 (2H, m), 1.30 (9H, s), 2.39 (3H, s), 7.23–7.39 (3H, m), 7.65 (1H, s).

[1311] Step 2: tert-butyl {l-[4-(2-aminopyrimidin-5-yl)-2-methylphenyl]cyclopropyl}carbamate

[1312]

[1313] Prepared similar as described in step 1, intermediate 13 using 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (73 mg, 0.09 mmol) from tert-butyl [l-(4-bromo-3-methylphenyl)cyclopropyl]carbamate (290 mg, 0.89 mmol) and 5-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (197 mg, 0.89 mmol, CAS RN 402960-38-7). White solid (250 mg, 83 %):XH NMR (500 MHz, DMSO) 60.94 (2H, d), 1.04 (2H, d), 1.32 (9H, s), 2.46 (3H, d), 6.72 (2H, s), 7.29–7.38 (2H, m), 7.49 (1H, d), 7.60 (1H, d), 8.54 (2H, d).Step 3: l-[4-(2-aminopyrimidin-5-yl)-2-methylphenyl]cyclopropan-l-aminium chloride (intermediate 27)

[1314] Prepared similar as described in step 3, intermediate 25 and used in the next step without further purification. White solid (32 mg, 79 %):1H NMR (500 MHz, DMSO) δ 1.09–1.13 (2H, m), 1.4–1.43 (2H, m), 2.54 (3H, s), 7.24 (1H, s), 7.5-7.55 (2H, m), 7.57 (1H, d), 8.57 (2H, s), 8.69 (2H, s).

[1315] Intermediate 28. 5-[5-(l-aminocyclopropyl)-3-methylpyridin-2-yl]pyrimidin-2-amine

[1316]

[1317] Step 1: tert-butyl [l-(6-bromo-5-methylpyridin-3-yl)cyclopropyl]carbamate

[1318]

[1319] Titanium isopropoxide (6.35 g, 22.33 mmol) was added dropwise to 6-bromo-5-methylpyridine-3-carbonitrile (4 g, 20.30 mmol) in diethyl ether (100 mL) at 0°C over a period of 10 minutes under nitrogen. Ethylmagnesium bromide in solution of THF (14.9 mL, 44.7 mmol) was added dropwise and the resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was then cooled to 0 °C and boron trifluoride etherate in diethyl ether (14.41 g, 40.60 mmol) was added and stirred another 2 h, then concentrated. To the residue was added potassium carbonate (2.81 g, 20.30 mmol) in water (10 mL), Di-tert-butyl dicarbonate (6.65 g, 30.45 mmol) and tetrahydrofurane (20mL) and the resulting reaction mixture was stirred at rt for 4 h, then water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (3 x 25 mL), and the combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash C18 chromatography of the residue using acetonitrile in water followed by concentration of the appropriate fractions gave the title compound as a yellow solid (3.30 g, 50 %):1H NMR (300 MHz, DMSO, 22 °C) 61.07-1.19 (4H, m), 1.36 (9H, s), 2.28 (3H, s), 7.45 (1H, d), 7.78 (1H, s), 8.00 (1H, s).

[1320] Step 2: tert-butyl {l-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}carbamate

[1321]

[1322] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (49.9 mg, 0.06 mmol) was added to tert-butyl [l-(6-bromo-5-methylpyridin-3-yl)cyclopropyl]carbamate (200mg, 0.61 mmol), potassium carbonate (169 mg, 1.22 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (203 mg, 0.92 mmol, CAS RN 402960-38-7) in dioxane (7 mL) and water (1.25 mL) at rt under nitrogen. The resulting mixture was stirred at 90 °C for 2 hours. Then allowed to cool to rtand filtered through celite. The mixture was filtered through a Celite pad and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.5 % formic acid (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a white (190 mg, 91 %): 1H NMR (300 MHz, DMSO) 61.13-1.24 (4H, m), 1.40 (9H, s), 2.35 (3H, s), 6.83 (2H, s), 7.36 (1H, s), 7.79 (1H, s), 8.28 (1H, d), 8.47 (2H, s).

[1323] Step 3: 5-[5-(l-aminocyclopropyl)-3-methylpyridin-2-yl]pyrimidin-2-amine (intermediate 28)

[1324] Trifluoroacetic acid (1.5 mL, 19.5 mmol) was added to a solution of tert-butyl {l-[6-(2-aminopyrimidin-5- yl)-5-methylpyridin-3-yl]cyclopropyl}carbamate (180 mg, 0.53 mmol) in dichloromethane (5 mL) at rt. The resulting mixture was stirred at rt for 1 h, then concentrated, redissolved in methanol and the pH was adjusted to ~8 by addition of aq. saturated sodium carbonate. Flash C-18 chromatography of the residue using acetonitrile in water with 0.1 % ammonium bicarbonate (0-25 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (87 mg) which was used directly in the next step without further purification.

[1325] Intermediate 29. 5-[6-(l-aminocyclopropyl)-2-methylpyridin-3-yl]pyrimidin-2-amine

[1326]

[1327] ^^AA

[1328] Step 1: l-(5-bromo-6-methylpyridin-2-yl)cyclopropan-l-amine

[1329] zS^frBr

[1330] ^^ A

[1331] Titanium isopropoxide (8.25 mL, 27.91 mmol) was added dropwise to 5-bromo-6-methylpyridine-2- carbonitrile (5 g, 25.38 mmol) in diethyl ether (75 mL) at -78°C under nitrogen and stirred for 5 min. 3M ethylmagnesium bromide in diethyl ether (18.6 mL, 55.8 mmol) was added dropwise and after 30 mins, the reaction mixture was warmed to rt and stirred another 1 h. Then, boron trifluoride etherate in diethyl ether (6 mL, 51 mmol) was added, and the mixture was stirred another 2 hours at rt. The reaction mixture was then washed with diethyl ether (1 x 150 mL) and the aq. layer was then basified (~ pH 10) using aq. saturated sodium carbonate, then extracted with dichloromethane (3 x 250 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated to provide crude title compound as a yellow solid (3.0 g, 52 %) which was used directly in the next step without further purification.

[1332] Step 2: tert-butyl [l-(5-bromo-6-methylpyridin-2-yl)cyclopropyl]carbamate

[1333]

[1334] Di-tert-butyl dicarbonate (5.67 g, 25.98 mmol) was added to l-(5-bromo-6-methylpyridin-2-yl)cyclopropan-l-amine (2.95 g, 13 mmol) and triethylamine (2.72 mL, 19.48 mmol) in dichloromethane (30 mL). The resulting mixture was stirred at rt for 2 h, then diluted with dichloromethane (200 mL), washed successively with water (1 x 100 mL) and brine, dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-25 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (2.0 g, 47 %):TH NMR (500 MHz, DMSO) 6 1.11 (2H, q), 1.21-1.31 (2H, m), 1.40 (9H, d), 2.49 (3H, s), 7.09 (1H, d), 7.78 (1H, s), 7.90 (1H, d).

[1335] Step 3: tert-butyl {l-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}carbamate

[1336]

[1337] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (0.424 g, 0.52 mmol) was added to tert-butyl [l-(5-bromo-6-methylpyridin-2-yl)cyclopropyl]carbamate (1.7 g, 5.20 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.38 g, 6.23 mmol, CAS RN 402960-38-7) and potassium carbonate (1.436 g, 10.39 mmol) in dioxane (25 mL) and water (5 mL). The resulting mixture was stirred at 90 °C for 2 hours under nitrogen. The reaction was then allowed to cool to rt and filtered through celite and combined with a parallel batch starting from 200 mg, 0.61 mmol tert-butyl [l-(5-bromo-6-methylpyridin-2-yl)cyclopropyl]carbamate and concentrated.

[1338] Flash chromatography of the residue using ethyl acetate in petroleum ether (0-68 %) followed by concentration of the appropriate fractions gave the title compound as a brown solid (1.6 g, 80 %):1H NMR (500 MHz, DMSO) 6 1.08-1.17 (2H, m), 1.27-1.46 (11H, m), 2.38 (3H, s), 6.77 (2H, s), 7.22 (1H, d), 7.54 (1H, d), 7.77 (1H, s), 8.28 (2H, s).

[1339] Step 4: 5-[6-(l-aminocyclopropyl)-2-methylpyridin-3-yl]pyrimidin-2-amine (intermediate 29)

[1340] A solution of tert-butyl {l-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}carbamate (1.58 g, 4.63 mmol) in 4 M hydrochloric acid in dioxane (20 mL) was stirred at rt for 2 h, then basified to pH 9 using aq. 1.5 M sodium hydroxide, then extracted using 3:1 chloroform-isopropanol (4 x 150 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated to provide the crude title compound as a brown solid (0.97 g, 87 %):XH NMR (500 MHz, DMSO) 60.95 (2H, q), 1.22 (2H, q), 2.38 (3H, s), 6.77 (2H, s), 7.54 (1H, d), 7.61 (1H, d), 8.27 (2H, s).

[1341] Intermediate 30. l-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropan-l-aminium chloride

[1342]

[1343] Step 1: tert-butyl [l-(5-bromo-4-methylpyridin-2-yl)cyclopropyl]carbamate

[1344]

[1345] Prepared similar as described in step 1, intermediate 28 from 5-bromo-4-methylpyridine-2-carbonitrile (500 mg, 2.54 mmol). Yellow oil (163 mg, 19 %):1H NMR (300 MHz, DMSO, 23°C) δ 1.13 (2H, q), 1.19–1.44 (11H, m), 2.35 (3H, d), 7.29 (1H, d), 7.78 (1H, s), 8.47 (1H, s).

[1346] Step 2: tert-butyl {l-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropyl}carbamate

[1347]

[1348] Prepared similar as described in step 2, intermediate 28 from tert-butyl [l-(5-bromo-4-methylpyridin-2-yl)cyclopropyl]carbamate (150 mg, 0.46 mmol). White solid (120 mg, 77 %):1H NMR (300 MHz, DMSO, 22°C) 6 1.11 (2H, q), 1.27 (2H, d), 1.43 (9H, s), 2.27 (3H, s), 6.80 (2H, s), 7.21 (1H, s), 7.79 (1H, s), 8.21 (1H, s), 8.28 (2H, s).

[1349] Step 3: l-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropan-l-aminium chloride (intermediate 30)

[1350] Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropyl}carbamate (110 mg, 0.32 mmol). White solid (100 mg, 99 %):1H NMR (500 MHz, DMSO) δ 1.35–1.52 (2H, m), 1.59 (2H, d), 2.34 (3H, s), 7.36 (1H, s), 8.43 (1H, s), 8.73 (2H, d), 9.18 (3H, s).

[1351] Intermediate 31. l-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-2-yl]cyclopropan-l-aminium chloride

[1352]

[1353] Step 1: tert-butyl [l-(5-chloro-6-methylpyrazin-2-yl)cyclopropyl]carbamate

[1354]

[1355] Prepared similar as described in step 1, intermediate 28 from 5-chloro-6-methylpyrazine-2-carbonitrile (2.3 g, 15 mmol). Brown oil (0.48 g, 11 %).

[1356] Step 2: tert-butyl {l-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-2-yl]cyclopropyl}carbamate

[1357]

[1358] Dichlorobis(tricyclohexylphosphine)palladium (II) (59.8 mg, 0.08 mmol) was added to a mixture of CsF (369 mg, 2.43 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (269 mg, 0.81 mmol, CAS RN 402960-38-7) and tert-butyl [l-(5-chloro-6-methylpyrazin-2-yl)cyclopropyl]carbamate (230 mg, 0.81 mmol) in dioxane (6 mL) and water (2 mL) at 25°C under nitrogen, then heated to 120 °C for 12 hours. The reaction mixture was filtered and the solids washed with methanol. Flash C-18 chromatography of the concentrated filtrates using acetonitrile in water with 0.05 % formic acid (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a brown oil (200 mg, 72 %):1H NMR (300 MHz, DMSO, 24°C) δ 1.02–1.11 (2H, m), 1.15–1.2 (2H, m), 1.43 (9H, s), 2.54 (3H, s), 6.97 (2H, s), 7.90 (1H, s), 8.26 (1H, s), 8.42 (1H, s), 8.54 (2H, s).

[1359] Step 3: l-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-2-yl]cyclopropan-l-aminium chloride (intermediate 31).

[1360] Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[5-(2-aminopyrimidin-5-yl)-6- methylpyrazin-2-yl]cyclopropyl}carbamate (190 mg, 0.55 mmol). The obtained title compound was used without further purification in the next step. Brown oil (140 mg).

[1361] Intermediate 32: l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropan-l- aminium chloride

[1362]

[1363] Step 1: tert-butyl (l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropyl)carbamate

[1364]

[1365] Prepared similar as described in step 1, intermediate 13 from tert-butyl [l-(5-bromo-6-methylpyridin-2- yl)cyclopropyl]carbamate (100 mg, 0.31 mmol, prepared as described in step 2, intermediate 29) and 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (82 mg, 0.34 mmol, CAS RN 1206640-82-5).1H NMR (400 MHz, DMSO, 22°C) δ 1.12 (2H, q), 1.37–1.48 (11H, m), 2.52 (3H, s), 7.21–7.29 (1H, m), 7.7–7.9 (3H, m), 8.11 (1H, s), 8.53 (1H, s).

[1366] Step 2: l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropan-l-aminium chloride (intermediate 32)Prepared similar as described in step 3, intermediate 16 from tert-butyl (l-{5-[l-(difluoromethyl)-lH- pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropyl)carbamate (50 mg, 0.14 mmol). The obtained title compound was used without further purification in the next step.

[1367] Intermediate 33. l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropan-l- aminium chloride

[1368]

[1369] Step 1: tert-butyl (l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropyl)carbamate

[1370]

[1371] Prepared similar as described in step 2, intermediate 31 from tert-butyl [l-(5-chloro-6-methylpyrazin-2- yl)cyclopropyl]carbamate (150 mg, 0.53 mmol, prepared as described in step 1, intermediate 31) and 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (155 mg, 0.63 mmol, CAS RN 1206640-82-5). Brown solid (100 mg, 52 %): 1H NMR (300 MHz, DMSO, 24°C) 6 1.19 (2H, s), 1.28 (2H, s), 1.43 (9H, s), 2.63 (3H, s), 3.17 (1H, d), 7.90 (1H, d), 8.31 (1H, s), 8.40 (1H, s), 8.72 (1H, s).

[1372] Step 2: l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropan-l-aminium chloride (intermediate 33)

[1373] Prepared similar as described in step 3, intermediate 16 from tert-butyl (l-{5-[l-(difluoromethyl)-lH- pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropyl)carbamate (100 mg, 0.27 mmol). The obtained title compound was used without further purification in the next step.

[1374] Intermediate 34. tert-butyl [l-(6-bromo-5-methylpyridin-3-yl)cyclopropyl]carbamate

[1375]

[1376] V

[1377] Titanium isopropoxide (6.35 g, 22.33 mmol) was added dropwise to 6-bromo-5-methylpyridine-3- carbonitrile (4 g, 20.30 mmol) in diethyl ether (100 mL) at 0°C over a period of 10 minutes under nitrogen. To the resulting reaction mixture was dropwise added 3 M ethyl magnesium bromide in tetrahydrofurane (14.9 mL, 44.7 mmol) and the reaction mixture was allowed to reach rt an stirred for 12 h at rt. Then the rm was cooled to 0 C and boron trifluoride etherate in diethyl ether (14.41 g, 40.60 mmol) was added and the

[1378] resulting mixture was stirred at 0 °C for 2 h, then concentrated. The residue was redissolved in tetrahydrofurane (20 mL) and was added potassium carbonate (2.81 g, 20.30 mmol) in water (10 mL) and di-tert-butyl dicarbonate (6.65 g, 30.45 mmol), then stirred at rt for 4 h.The reaction mixture was then diluted with water (100 mL), extracted with ethyl acetate (3 x 25 mL) and the combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (3.30 g, 50 %):1H NMR (300 MHz, DMSO, 22°C) 6 1.07-1.19 (4H, m), 1.36 (9H, s), 2.28 (3H, s), 7.45 (1H, d), 7.78 (1H, s), 8.00 (1H, s).

[1379] Intermediate 35. l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropan-l-aminium chloride

[1380]

[1381] Step 1: tert-butyl (l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)carbamate

[1382]

[1383] 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (125 mg, 0.15 mmol) was added to intermediate 34 (500mg, 1.53 mmol), l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (559 mg, 2.29 mmol, CAS RN 1206640-82-5) and potassium carbonate (422 mg, 3.06 mmol) in water (2 mL) and dioxane (10 mL) at rt under nitrogen. The resulting mixture was stirred at 90 °C for 16 hours, then allowed to reach rt and filtered through celite and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (380 mg, 68 %):1H NMR (300 MHz, DMSO, 22°C) 6 1.16 (4H, ddd), 1.38 (9H, s), 2.42 (3H, s), 7.33 (1H, s), 7.61-8.09 (2H, m), 8.25 (2H, d), 8.59 (1H, s).

[1384] Step 2: l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropan-l-aminium chloride (intermediate 35).

[1385] Prepared similar as described in step 3, intermediate 16 from tert-butyl (l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)carbamate (360 mg, 0.99 mmol). The product obtained after concentration of the reaction mixture (yellow oil) was used as such without further purification in the next step.

[1386] Intermediate 36. l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropan-l-aminium chloride

[1387]

[1388] Step 1: tert-butyl [l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropyl]carbamate

[1389]

[1390] Prepared similar as described in step 1, intermediate 35 from intermediate 34 (100 mg, 0.31 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (81 mg, 0.37 mmol, CAS RN 827614-64-2). White solid (70 mg, 67 %):1H NMR (300 MHz, DMSO, 21°C) δ 1.12 (2H, d), 1.16 (2H, s), 1.38 (9H, s), 2.30 (3H, s), 6.09 (2H, s), 6.48 (1H, d), 7.30 (1H, s), 7.58 (1H, dd), 7.77 (1H, s), 8.10 (1H, d), 8.23 (1H, s).

[1391] Step 2: l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropan-l-aminium chloride (intermediate 36) Prepared similar as described in step 3, intermediate 16 from tert-butyl [l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropyl]carbamate (60 mg, 0.18 mmol). The product obtained after concentration of the reaction mixture (white solid) was used as such without further purification in the next step.

[1392] Intermediate 37. 4-{4-[5-(l-azaniumylcyclopropyl)-3-methylpyridin-2-yl]-lH-pyrazol-l-yl}-l-methylpiperidin-l-ium dichloride

[1393]

[1394] Step 1: tert-butyl (l-{5-methyl-6-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)carbamate

[1395]

[1396] Prepared similar as described in step 1, intermediate 35 from intermediate 34 (112 mg, 0.34 mmol) and l-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine (81 mg, 0.37 mmol, CAS RN 1323919-64-7). Yellow solid (70 mg, 50 %):1H NMR (300 MHz, DMSO, 23°C) δ 1.12–1.2 (4H, m), 1.39 (9H, s), 2.02 (8H, q), 2.22 (3H, d), 2.41 (3H, s), 4.15–4.23 (1H, m), 7.28 (1H, s), 7.76 (1H, s), 7.91 (1H, s), 8.20 (2H, d).

[1397] Step 2: 4-{4-[5-(l-azaniumylcyclopropyl)-3-methylpyridin-2-yl]-lH-pyrazol-l-yl}-l-methylpiperidin-l-ium dichloride (intermediate 37)

[1398] Prepared similar as described in step 3, intermediate 16 from tert-butyl (l-{5-methyl-6-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)carbamate (50 mg, 0.12 mmol). The product obtained after concentration of the reaction mixture (grey solid) was used as such without further purification in the next step.Intermediate 38. l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropan-l-aminium chloride

[1399]

[1400] Step 1: tert-butyl (l-{5-methyl-6-[2-(oxan-2-yl)-2H-1,2,3-triazol-4-yl]pyridin-3-yl}cyclopropyl)carbamate

[1401]

[1402] Prepared similar as described in step 1, intermediate 35 from intermediate 34 (400 mg, 1.22 mmol) and 2-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-l,2,3-triazole

[1403] (512 mg, 1.83 mmol, CAS RN 1415312-45-6). White solid (378 mg, 77 %):1H NMR (300 MHz, DMSO, 21°C) δ 1.12–1.19 (2H, m), 1.21 (2H, d), 1.38 (9H, s), 1.52–1.66 (2H, m), 1.65–1.83 (1H, m), 2.03 (2H, d), 2.29 (1H, q), 2.55 (3H, s), 3.70 (1H, dt), 3.87 (1H, dd), 5.80 (1H, dd), 7.38 (1H, s), 7.81 (1H, s), 8.24 (1H, s), 8.29 (1H, s).

[1404] Step 2: tert-butyl {l-[5-methyl-6-(2H-1,2,3-triazol-4-yl)pyridin-3-yl]cyclopropyl}carbamate

[1405]

[1406] 4-methylbenzenesulfonic acid (160 mg, 0.93 mmol) was added to tert-butyl (l-{5-methyl-6-[2-(oxan-2-yl)-2H-1,2,3-triazol-4-yl]pyridin-3-yl}cyclopropyl)carbamate (310 mg, 0.78 mmol) in methanol (5 mL) and the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was then allowed to cool to rt and pH was adjusted to pH 8 using aq. saturated sodium carbonate. Flash C-18 chromatography of the crude using acetonitrile in water with 0.1 % ammonium bicarbonate (0-50 %) followed by concentration of the appropriate fraction gave the title compound as a pale yellow solid (190 mg, 78 %):1H NMR (300 MHz, DMSO, 21°C) δ 1.11–1.18 (2H, m), 1.20 (2H, d), 1.38 (9H, s), 2.53 (3H, s), 7.37 (1H, s), 7.80 (1H, s), 8.22 (1H, s), 8.28 (1H, d), 15.13 (1H, s).

[1407] Step 3: tert-butyl (l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)carbamate

[1408]

[1409] Sodium chlorodifluoroacetate (109 mg, 0.71 mmol) was added to tert-butyl {l-[5-methyl-6-(2H-1,2,3-triazol-4-yl)pyridin-3-yl]cyclopropyl}carbamate (150 mg, 0.48 mmol) and caesium carbonate (465 mg, 1.43 mmol) in N, N-dimethylformamide (3 mL) and the resulting mixture was stirred at 70 °C for 15 hours under nitrogen. The reaction mixture was allowed to cool to rt, diluted with ethyl acetate (50 mL), andwashed successively with water (3 x 10 mL) and brine (1 x 15 ml), then dried (sodium sulphate), filtered and concentrated.

[1410] Flash chromatography of the residue using ethyl acetate in petroleum ether (0-36 %) followed by concentration of the pure fractions gave first tert-butyl (l-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)carbamate

[1411] a pale yellow solid (50 mg, 29 %): 1H NMR (500 MHz, DMSO) 61.18-1.23 (2H, m), 1.25-1.28 (2H, m), 1.40 (9H, s), 2.57 (3H, s), 7.42-7.47 (1H, m), 7.85 (1H, d), 8.11-8.31 (1H, m), 8.35 (1H, t), 8.59 (1H, s). Concentration of subsequent pure fractions gave the title compound as a white solid (40 mg, 23 %):1H NMR (500 MHz, DMSO) 61.16-1.21 (2H, m), 1.21-1.26 (2H, m), 1.40 (9H, s), 2.58 (3H, s), 7.41 (1H, s), 7.82 (1H, s), 8.16-8.43 (2H, m), 9.06 (1H, s).

[1412] Step 4: l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropan-l-aminium chloride (intermediate 38)

[1413] Prepared similar as described in step 3, intermediate 16 from tert-butyl (l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)carbamate (75 mg, 0.21 mmol). The product obtained after concentration of the reaction mixture (white solid) was used as such without further purification in the next step.

[1414] Intermediate 39. l-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropan-l-amine

[1415]

[1416] Prepared similar as described in step 3, intermediate 16 from tert-butyl (l-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)carbamate (75 mg, 0.21 mmol, obtained as described in step 3, intermediate 38). The pH of the reaction mixture was adjusted to 8 by addition of aq. saturated sodium carbonate. Flash C-18 chromatography of the crude using acetonitrile in water with 0.1 % ammonium bicarbonate (0-45 %) followed by concentration of the appropriate fraction gave the title compound as a white solid (50 mg, 92 %):1H NMR (500 MHz, DMSO) δ 1.04 (4H, s), 2.58 (3H, s), 2.67 (2H, s), 7.67 (1H, d), 8.22 (1H, t), 8.50 (1H, d), 8.58 (1H, s).

[1417] Intermediate 40. l-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropan-l-aminium chloride

[1418]

[1419] Step 1: tert-butyl [l-(6-bromo-5-chloropyridin-3-yl)cyclopropyl]carbamatePrepared similar as described in steps 1 and 2 of intermediate 29 from 6-bromo-5-chloropyridine-3-carbonitrile (3 g, 13.8 mmol, CAS RN 1256790-78-9). White solid (0.86 g, 51 %):1H NMR (500 MHz, DMSO) δ 1.17 (2H, q), 1.28 (2H, d), 1.38 (9H, s), 7.71 (1H, s), 7.85 (1H, s), 8.16 (1H, d).

[1420] Step 2: tert-butyl {l-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropyl}carbamate

[1421]

[1422] Prepared similar as described in step 3, intermediate 29 from 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (191 mg, 0.86 mmol, CAS RN 402960-38-7) and tert-butyl [l-(6-bromo-5-chloropyridin-3-yl)cyclopropyl]carbamate (200 mg, 0.58 mmol). White solid (200 mg, 96 %):1H NMR (300 MHz, DMSO, 23°C) δ 1.17 (2H, dt), 1.26 (2H, dd), 1.38 (9H, s), 7.00 (2H, s), 7.63 (1H, d), 7.86 (1H, s), 8.36 (1H, d), 8.59 (2H, s).

[1423] Step 3. l-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropan-l-aminium chloride (intermediate 40).

[1424] Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropyl}carbamate (190 mg, 0.53 mmol). The product obtained after concentration of the reaction mixture (white solid) was used as such without further purification in the next step.

[1425] Intermediate 41. l-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropan-l-aminium chloride

[1426]

[1427] Step 1: 5-bromo-2-chloro-3-ethenylpyridine

[1428]

[1429] Potassium tert-butoxide (1.83 g, 16.3 mmol) was added to methyltriphenylphosphonium bromide (6.08 g, 17.01 mmol) in toluene (40 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0 °C for 1 hour under nitrogen the n cooled to -20 °C after which a solution of 5-bromo-2-chloropyridine-3-carbaldehyde (3 g, 13.61 mmol) in tetrahydrofurane (10 mL) was added. The resulting mixture was warmed to 0 °C and stirred for 1 h.

[1430] The reaction mixture was then quenched with aq. saturated ammonium chloride (50 mL), extracted with ethyl acetate (2 x 100 mL) and the combined organic layers was dried (sodium sulphate), filtered andconcentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-19 %) followed by concentration of the appropriate fractions gave the title compound as a pale yellow liquid (2.2 g, 74.0 %):1H NMR (300 MHz, DMSO, 23°C) δ 5.6–5.69 (1H, m), 6.16 (1H, dd), 6.87 (1H, dd), 8.45 (1H, d), 8.49 (1H, d).

[1431] Step 2: 5-bromo-2-chloro-3-ethylpyridine

[1432]

[1433] Tris(triphenylphosphine)rhodium(l) chloride (0.745 g, 0.81 mmol) was added to 5-bromo-2-chloro-3- ethenylpyridine (2.2 g, 10.07 mmol) in EtOH (30 mL) under nitrogen. The resulting mixture was stirred at 60 °C for 15 hours under an atmosphere of hydrogen, then filtered through celite and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-21 %) followed by concentration of the appropriate fractions gave the title compound as a pale-yellow liquid (1.7 g, 77 %):1H NMR (500 MHz, DMSO) δ 1.19 (3H, t), 2.69 (2H, q), 8.08–8.1 (1H, m), 8.42 (1H, d).

[1434] Step 3: tert-butyl [l-(6-chloro-5-ethylpyridin-3-yl)cyclopropyl]carbamate

[1435]

[1436] Prepared similar as described in step 1 for intermediate 25 from 5-bromo-2-chloro-3-ethylpyridine (460 mg, 2.09 mmol). White solid (280 mg, 45 %): 1H NMR (500 MHz, DMSO) δ 1.13–1.23 (7H, m), 1.38 (9H, s), 2.66 (2H, q), 7.45 (1H, d), 7.80 (1H, s), 8.02 (1H, d).

[1437] Step 4: tert-butyl {l-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropyl}carbamate

[1438] •°YN2^-

[1439]

[1440] Prepared similar as described in step 3, intermediate 12 from tert-butyl [l-(6-chloro-5-ethylpyridin-3- yl)cyclopropyl]carbamate (220 mg, 0.74 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-amine (197 mg, 0.89 mmol, CAS RN 402960-38-7). White solid (220 mg 84 %): 1H NMR (500 MHz, DMSO) δ 1.12 (3H, t), 1.14–1.18 (2H, m), 1.21 (2H, d), 1.40 (9H, s), 2.65 (2H, q), 6.81 (2H, s), 7.35–7.52 (1H, m), 7.80 (1H, s), 8.25 (1H, d), 8.38 (2H, s).

[1441] Step 5: l-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropan-l-aminium chloride (intermediate 41)Prepared similar as described in step 3, intermediate 16 from tert-butyl {l-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropyl}carbamate (70 mg, 0.18 mmol). The product obtained after concentration of the reaction mixture (white solid) was used as such without further purification in the next step.

[1442] Intermediate 42. tert-butyl 4-{4-[3-methyl-5-(l-{[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carbonyl]amino}cyclopropyl)pyridin-2-yl]-lH-pyrazol-l-yl}piperidine-l-carboxylate

[1443] Step 1: l-(6-bromo-5-methylpyridin-3-yl)cyclopropan-l-amine

[1444]

[1445] Intermediate 34 (450 mg, 1.38 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) and stirred at rt for 1 h, then concentrated. The residue was dissolved in methanol and basified with sodium carbonate. Flash C-18 chromatography of the mixture using acetonitrile in water (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (134 mg, 4

[1446]

[1447] 3 %): NMR (300 MHz, DMSO, 21°C) δ 0.87–1.04 (4H, m), 2.28 (3H, s), 2.40 (2H, s), 7.59 (1H, dd), 8.17 (1H, d).

[1448] Step 2: tert-butyl 4-{4-[5-(l-aminocyclopropyl)-3-methylpyridin-2-yl]-lH-pyrazol-l-yl}piperidine-l-carboxylate

[1449]

[1450] Prepared similar as described in step 1, intermediate 35 from l-(6-bromo-5-methylpyridin-3-yl)cyclopropan-l-amine (100 mg, 0.44 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate

[1451] (183 mg, 0.48 mmol, CAS RN 877399-74-1). Colourless oil (90 mg, 51 %):1H NMR (300 MHz, DMSO, 22°C) δ 0.94 (4H, q), 1.41 (9H, s), 1.83 (2H, qd), 2.02 (2H, d), 2.40 (3H, s), 2.90 (2H, s), 4.04 (2H, q), 4.34–4.5 (1H, m), 7.47 (1H, d), 7.90 (1H, s), 8.17 (1H, s), 8.33 (1H, d).

[1452] Step 3: tert-butyl 4-{4-[3-methyl-5-(l-{[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carbonyl]amino}cyclopropyl)pyridin-2-yl]-lH-pyrazol-l-yl}piperidine-l-carboxylate (intermediate 42)Prepared similar as described in example 83 from intermediate 1 (35 mg, 0.15 mmol) and tert-butyl 4-{4- [5-(l-aminocyclopropyl)-3-methylpyridin-2-yl]-lH-pyrazol-l-yl}piperidine-l-carboxylate (60 mg). Yellow oil (23 mg, 25 %) which was used directly in the next step.

[1453] Intermediate 43. 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-amine

[1454]

[1455] o

[1456] Step 1: / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide

[1457]

[1458] A pale yellow solution of 2,5-dibromo-3-methylpyridine (20 g, 79.71 mmol, CAS RN 3430-18-0) in tetrahydrofurane (400 mL) was cooled to ca. -78°C on a cardice / acetone bath. 1.6 M butyllithium in hexanes (46.5 mL, 74.39 mmol, 1.4 eq) was added dropwise over ca. 15 minutes by syringe pump (flow rate 3.0 mL / min), to give a dark brown solution. The reaction was stirred at -78 °C for one hour before a dark brown solution of 2-methyl- / V-(oxetan-3-ylidene)propane-2-sulfinamide (9.31 g, 53.14 mmol, CAS RN 1158098-73-7) in tetra hydrofuran (50 mL) was added dropwise at -78 °C over ca. 5 minutes by syringe pump (flow rate 10 mL / min). Once the addition was complete, the reaction solution was stirred for 10 min at -78 °C before the cold bath was removed and the reaction was allowed to warm to room temperature. The reaction was stirred at room temperature for 1 h before quenching by pouring into 10% aq. ammonium chloride solution (250 mL). The mixture was diluted with water (500 mL) and extracted into ethyl acetate (2 x 250 mL). The organic layers were combined and washed with brine (1 x 50 mL), dried (magnesium sulphate), filtered and concentrated which afforded 22 g of a dark brown syrup. Flash chromatography of the residue using ethyl acetate in heptane (75 %, isocratic elution) followed by concentration of the appropriate fractions (detected by thin layer chromatography, 9:1 ethyl acetate-heptane) to give the title compound as a pale orange solid (5.98 g, 32 %):1H NMR (500 MHz, CDCI3, 25°C) δ 1.19 (9H, s), 2.40 (3H, s), 4.33 (1H, d), 4.84 (1H, d), 5.00 (1H, d), 5.06 (1H, d), 5.11 (1H, d), 7.59 (1H, d), 8.22 (1H, d). m / z (ES+) [M+H]+ = 347.1 and 349.1.

[1459] Step 2: / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-2-methylpropane- 2-sulfinamide

[1460]

[1461] l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.32 g, 25.92 mmol, CAS RN 1206640-82-5) and / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide(6.00 g, 17.28 mmol) were combined as an orange solution in ethanol (95%) (90 mL) under an atmosphere of nitrogen. XPhos Pd G3 (0.731 g, 0.86 mmol,

[1462] CAS RN 1445085-55-1) was added, followed by aq. 2.0 M potassium carbonate (17.28 mL, 34.56 mmol). The brown mixture was warmed and stirred at 50°C for 2 h, then allowed to cool and concentrated. The residue was partitioned between ethyl acetate (200 mL) and water (100 mL) and the water layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (1 x 100 mL), brine (1 x 25 mL), then dried (magnesium sulphate), filtered and concentrated. Flash chromatography of the residue using first 1:1 ethyl acetate-heptane (5 column volumes) followed by gradient elution using ethyl acetate-heptane (50-100%) followed by concentration of the appropriate fractions gave the title compound as a pale yellow foam (6.35 g). The material was scavenged for residual palladium by dissolving the foam in ethyl acetate (125 mL) and stirring with 10 g Isolute Si-TMT (0.45 mmol / g, Biotage) at rt for 2 h, then filtered and concentrated to provide the title compound as a pale yellow foam (5.75 g, 87 %):1H NMR (500 MHz, DMSO, 25°C) δ 1.13 (9H, s), 2.50 (3H, s), 4.77 (1H, d), 4.91 (1H, d), 5.03 (2H, dd), 6.43 (1H, s), 7.7–8.05 (2H, m), 8.30 (1H, s), 8.56 (1H, d), 8.67 (1H, s).

[1463] Step 3: 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-amine (intermediate 43)

[1464] / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide (7.95 g, 20.68 mmol) was dissolved in tetrahydrofurane (100 mL) and cooled on an ice batch. To the chilled solution was added portionwise l,3-dibromo-5,5-dimethylimidazolidine-2, 4-dione (7.10 g, 24.81 mmol) over 5 minutes. The reaction mixture was stirred with cooling for 30 min, then quenched by slow addition of aq. saturated sodium hydrogen carbonate (100 mL) and monitor the pH by indicator strip to assure neutral pH was obtained. The mixture was concentrated to remove residual tetrahydrofurane, then diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL) and brine (1 x 25 mL), passed through a phase separator, and concentrated to provide a brown oil (~10 g).

[1465] The water layer was basified with aq. 3.8 M sodium hydroxide (~ 2 mL) and extracted into 9:1 dichloromethane-methanol (2 x 100 mL) and the combined organic layers were passed through a phase separator and concentrated to provide an orange gum (additional "'0.8 g). The residues were combined in dichloromethane and adsorbed onto silica (~40 g) which was loaded onto a preconditioned silica column. Flash chromatography using dichloromethane (3 column volumes), followed by gradient elution with methanol in dichloromethane (0-5 %, 15 column volumes) and isocratic (5 %, 15 column volumes). Concentration of the appropriate fractions gave the title compound as a pale yellow solid (4.3 g, 74 %):1H NMR (500 MHz, DMSO, 25°C) δ 2.66 (2H, s), 4.68 (2H, d), 4.76 (2H, d), 7.74–8.01 (2H, m), 8.29 (1H, s), 8.65 (1H, d), 8.67 (1H, d).Intermediate 44. 3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-amine

[1466]

[1467] Step 1: 2-methyl- / V-(3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)propane- 2-sulfinamide

[1468]

[1469] Prepared similar as described in step 2, intermediate 43 from 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(trifluoromethyl)-lH-pyrazole (377 mg, 1.44 mol, CAS RN 1046831-98-4). White solid (130 mg, 56 %):1H NMR (300 MHz, DMSO, 23°C) δ 1.14 (9H, s), 2.54 (3H, s), 4.71–5.12 (4H, m), 6.48 (1H, s), 7.87 (1H, dd), 8.43–8.48 (1H, m), 8.59 (1H, d), 8.87 (1H, s).

[1470] Step 2: 3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-amine (intermediate 44)

[1471] Prepared similar as described in step 3, intermediate 43 from 2-methyl- / V-(3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)propane-2-sulfinamide (120 mg, 0.30 mmol). White solid which was used directly in the next step.

[1472] Intermediate 45. 3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-amine

[1473]

[1474] Step 1: / V-{3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-yl}-2-methylpropane-2-sulfinamide

[1475]

[1476] Prepared similar as described in step 2, intermediate 43 from l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (CAS RN 1036991-40-8). White solid:1H NMR (300 MHz, DMSO, 23°C) δ 1.15 (9H, d), 1.24 (1H, s), 2.36 (3H, s), 3.80 (3H, s), 4.79 (1H, d), 4.92 (1H, d), 5.03 (2H, d), 7.65 (1H, s), 7.78 (1H, d), 8.55 (1H, d).

[1477] Step 2: 3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-amine (intermediate 45)

[1478] Prepared similar as described in step 3, intermediate 43 from / V-{3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-yl}-2-methylpropane-2-sulfinamide (90 mg, 0.25 mmol). White solid which was used directly in the next step (45 mg, 70 %).Intermediate 46. 3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-amine

[1479]

[1480] Step 1: 2-methyl- / V-{3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}propane-2-sulfinamide

[1481]

[1482] Prepared similar as described in step 2, intermediate 43 from l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (CAS RN 761446-44-0). White solid:1H NMR (300 MHz, DMSO, 23°C) δ 1.14 (9H, s), 1.24 (1H, s), 2.48 (3H, s), 3.92 (3H, s), 4.77 (1H, d), 4.92 (1H, d), 5.04 (2H, dd), 7.57 (1H, d), 7.96 (1H, d), 8.23 (1H, s), 8.50 (1H, d).

[1483] Step 2: 3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-amine (intermediate 46) Prepared similar as described in step 3, intermediate 43 from 2-methyl- / V-{3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}propane-2-sulfinamide (120 mg, 0.34 mmol). White solid (80 mg, 95 %): NMR (300 MHz, DMSO, 22°C) δ 2.46 (3H, s), 3.91 (3H, s), 4.66 (2H, d), 4.75 (2H, d), 7.93 (1H, d), 8.19 (1H, s), 8.32 (1H, s), 8.60 (1H, d).

[1484] Intermediate 47. 3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-amine

[1485] Step 1: 2-methyl- / V-{3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}propane-2-sulfinamide

[1486]

[1487] Prepared similar as described in step 2, intermediate 43 from 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (CAS RN 269410-08-4). White solid:1H NMR (300 MHz, DMSO, 23°C) δ 1.14 (9H, s), 1.24 (1H, s), 2.49 (3H, s), 4.85 (2H, dd), 5.04 (2H, dd), 7.75 (1H, d), 8.13 (2H, s), 8.51 (1H, d), 13.08 (1H, s).

[1488] Step 2: 3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-amine (intermediate 47).

[1489] Prepared similar as described in step 3, intermediate 43 from 2-methyl- / V-{3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}propane-2-sulfinamide (105 mg, 0.31 mmol). White solid which was used directly in the next step (45 mg, 62 %).Intermediate 48. 3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-amine

[1490]

[1491] / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (prepared as described in step 1, intermediate 43) was treated similar as described in step 2 of intermediate 43. Colourless oil:1H NMR (300 MHz, DMSO, 23°C) δ 2.36 (3H, s), 2.57 (1H, s), 2.92–3.11 (2H, m), 3.11–3.25 (2H, m), 4.79 (2H, t), 4.96 (2H, dd), 5.53–5.64 (1H, m), 5.77 (1H, s), 7.22–7.32 (2H, m), 7.33–7.47 (3H, m), 7.93 (1H, dd), 8.26–8.33 (1H, m), 9.78 (1H, s).

[1492] Intermediate 49. (5S)- / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1493]

[1494] Prepared similar as described in example 116 below, from intermediate 1 (754 mg, 3.29 mmol) and intermediate 48 (800 mg, 3.29 mmol). White solid (480 mg, 32 %): 1H NMR (300 MHz, DMSO, 23°C) 6 2.9-3.26 (3H, m), 4.73-5 (4H, m), 5.52-5.62 (1H, m), 7.19-7.47 (5H, m), 7.93 (1H, dd), 8.22-8.4 (1H, m), 9.78 (1H, s).

[1495] Intermediate 50. l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}methanamine

[1496]

[1497] Prepared similar as described in step 1, intermediate 13 from l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (364 mg, 1.49 mmol, CAS RN 1206640-82-5) and l-(6-bromo-5-methylpyridin-3-yl)methanamine (200 mg, 0.99 mmol, CAS RN 1355231-24-1). Brown gum (140 mg, 59 %): 1H NMR (300 MHz, DMSO, 23°C) δ 2.46 (3H, s), 3.75 (2H, s), 7.62–7.72 (1H, m), 7.97 (1H, d), 8.27 (1H, s), 8.40 (1H, d), 8.63 (1H, d).

[1498] Intermediate 51. l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methanamine

[1499]

[1500] Step 1: (6-bromo-5-methylpyridin-3-yl)(2H2)methanol

[1501]

[1502] Sodium borodeuteride (0.728 g, 17.39 mmol) was added to methyl 6-bromo-5-methylpyridine-3-carboxylate (2.0 g, 8.69 mmol, CAS RN 1210451-92-5) in EtOH (1 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours, then allowed to cool to rt and then applied to a C-18 column.Flash chromatography using acetonitrile in water (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (1.2 g, 68 %): 1H NMR (300 MHz, DMSO, 23°C) δ 2.33 (3H, s), 5.35 (1H, s), 7.69 (1H, dd), 8.15 (1H, dd).

[1503] Step 2: {6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methanol

[1504]

[1505] Prepared similar as described in step 1, intermediate 13 from l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (239 mg, 0.98 mmol, CAS RN 1206640-82-5) and (6-bromo-5-methylpyridin-3-yl)(2H2)methanol (200 mg, 0.98 mmol). White solid (160 mg, 68 %):1H NMR (300 MHz, DMSO, 22°C) δ 1.13 (9H, s), 2.37 (3H, s), 4.6–5.18 (4H, m), 6.48 (1H, s), 7.92 (1H, d), 8.34 (1H, d).

[1506] Step 3: 5-[azido(2H2)methyl]-2-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylpyridine

[1507]

[1508] l,8-Diazabicyclo[5.4.0]undec-7-ene (124 mg, 0.81 mmol) was added to {6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methanol (178 mg, 0.74 mmol) and diphenyl phosphoryl azide (223 mg, 0.81 mmol) in toluene (5 mL) under nitrogen. The resulting mixture was stirred at rt for 2 hours, then concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (121 mg, 62 %).

[1509] Step 4: l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methanamine (intermediate 51)

[1510] 5-(azidomethyl-d2)-2-(l-(difluoromethyl)-1H-pyrazol-4-yl)-3-methylpyridine (60 mg, 0.23 mmol) was added to triphenylphosphine (59 mg, 0.23 mmol) in water (1 mL) and THF (3 mL) under nitrogen. The resulting mixture was stirred at rt for 2 hours, then concentrated.

[1511] Flash C18 chromatography of the residue using acetonitrile in water (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (40 mg, 74 %): 1H NMR (300 MHz, DMSO, 23°C) δ 2.46 (3H, s), 7.65 (1H, d), 7.87 (1H, t), 8.27 (1H, s), 8.39 (1H, d), 8.62 (1H, s).

[1512] Intermediate 52. (l / ? S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethan-l-amine.

[1513]

[1514] Prepared similar as described in step 1, intermediate 13 from l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (567 mg, 2.32 mmol, CAS RN 1206640-82-5) and (lRS)-l-(6-bromo-5-methylpyridin-3-yl)ethan-l-amine (500 mg, 2.32 mmol, CAS RN 1337178-28-5). Colourless oil (400 mg, 68 %): 1H NMR (400 MHz, DMSO, 21°C) δ 1.28 (3H, d), 1.99 (2H, s), 2.45 (3H, s), 4.02 (1H, q), 7.67 (1H, d), 7.86 (1H, t), 8.25 (1H, s), 8.42 (1H, d), 8.60 (1H, d).

[1515] Intermediate 53. 2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-amine

[1516]

[1517] Step 1: 2-(6-bromo-5-methylpyridin-3-yl)propan-2-ol

[1518]

[1519] n-Butyllithium (8.13 mL, 20.33 mmol) was added to 2,5-dibromo-3-methylpyridine (5 g, 19.93 mmol) in THF (100 mL) at -78°C under nitrogen. The resulting mixture was stirred at -78 °C for 30 minutes, then acetone (1.5 g, 25.9 mmol) was added dropwise and the reaction mixture was stirred another 2 h. The reaction mixture was then quenched with aq. saturated ammonium chloride (50 mL), extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a colourless (2.5 g, 54 %

[1520]

[1521] ): NMR (300 MHz, DMSO, 21°C) δ 1.42 (6H, s), 2.31 (3H, d), 5.27 (1H, s), 7.80 (1H, dd), 8.27 (1H, dd).

[1522] Step 2: 2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-ol

[1523]

[1524] Prepared similar as described in step 1, intermediate 35 from l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1114 mg, 4.56 mmol, CAS RN 1206640-82-5) and 2-(6-bromo-5-methylpyridin-3-yl)propan-2-ol (700 mg, 3.04 mmol). Yellow oil (800 mg, 98 %):1H NMR (300 MHz, DMSO, 22°C) δ 1.45 (6H, s), 2.45 (3H, s), 5.19 (1H, s), 7.64–8.06 (2H, m), 8.24 (1H, d), 8.53 (1H, dd), 8.60 (1H, d).

[1525] Step 3: / V-(2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-yl)acetamide

[1526]

[1527] Sulfuric acid (0.53 mL, 9.95 mmol) was added to 2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-ol (380 mg, 1.42 mmol) in acetonitrile (6 mL) at 0 °C. The resulting mixture was stirred at rt for 20 hours, then diluted with ethyl acetate (50 mL), washed successively with water (1x 50 mL), brine (1 x 50 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (330 g, 75 %):1H NMR (300 MHz, DMSO, 22°C) 6 1.57 (6H, s), 1.85 (3H, s), 2.46 (3H, s), 7.56 (1H, d), 7.88 (1H, t), 8.18 (1H, s), 8.26 (1H, s), 8.40 (1H, d), 8.61 (1H, d).

[1528] Step 4: 2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-amine (intermediate 53)

[1529] Hydrochloric acid (3 mL, 98.74 mmol) was added to / V-(2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5- methylpyridin-3-yl}propan-2-yl)acetamide (300 mg, 0.97 mmol) in water (6 mL) at rt. The resulting mixture was stirred at 100 °C for 20 hours. The reaction mixture was basified to pH ~9 with aq. 2 M sodium hydroxide, then extracted with ethyl acetate (2 x 50 mL). The combined organic layers were then dried (sodium sulphate), filtered and concentrated providing crude title compound as a colourless oil (250 mg): 1H NMR (300 MHz, DMSO, 21°C) 6 1.39 (6H, s), 2.44 (3H, s), 7.64-8.06 (2H, m), 8.24 (1H, s), 8.59 (2H, dd).

[1530] Intermediate 54. rac-(l / ?,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2- methylcyclopropan-l-amine

[1531]

[1532] Step 1: tert-butyl [roc-(lR,2S)-l-(6-chloro-5-methylpyridin-3-yl)-2-methylcyclopropyl]carbamate (134-9- 015)

[1533]

[1534] Titanium(IV) isopropoxide (23 mL, 78.65 mmol) was added dropwise to 6-chloro-5-methylpyridine-3- carbonitrile (6 g, 39.32 mmol) in tetrahydrofurane (200 mL) at -78 °C over a period of 15 minutes under nitrogen and then stirred for additional 15 min after which propylmagnesium bromide (49.2 mL, 98.31 mmol) was added dropwise at -78°C over a period of 20 minutes under nitrogen and stirred additonal 30 minutes at this -78 °C. The resulting mixture was then stirred at rt for 16 hours. The reaction mixture was then quenched with aq. 1 M NaOH (50 mL), diluted with water (100 mL), then extracted into ethyl acetate (2 x 100 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-100 %) followed by concentration of product containing fractions gave a yellow oil. This material was combined with residues from 2 similar batches starting from 6-chloro-5-methylpyridine-3-carbonitrile (3 g, 19.7 mmol) and flash chromatography using methanol in dichloromethane (0-10 %) followed by concentration of product containing fractions gave 1.2 g of a yellow oil of 50 % purity. The yellow oil wasdissolved in dichloromethane (20 mL) and treated with di-tert-butyl decarbonate (1.6 g, 7.32 mmol) and triethyl amine (1.7 mL, 12.2 mmol) for 16 h at rt, then concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.50 g):1H NMR (300 MHz, DMSO, 21°C) 60.69 (3H, d), 0.99 (1H, dd), 1.13 (1H, t), 1.30 (9H, s), 1.37 (1H, td), 2.31 (3H, s), 7.69 (1H, dd), 7.74 (1H, s), 8.19 (1H, d).

[1535] Step 2: tert-butyl [roc-(lR,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]carbamate

[1536] Prepared similar as described in step 3, intermediate 12 from l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (395 mg, 1.62 mmol, CAS RN 1206640-82-5) and tert-butyl [rac-(lR,2S)-l-(6-chloro-5-methylpyridin-3-yl)-2-methylcyclopropyl]carbamate (400 mg, 1.35 mmol). White solid (380 mg, 74%): m / z (ES+) [M+H]+ = 379.15.

[1537] Step 3: roc-(lR,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropan-1-amine (intermediate 54)

[1538] 4 M HCI in dioxane (10 ml, 40 mmol) was added to tert-butyl [roc-(lR,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]carbamate (370mg, 0.98 mmol) at rt. The resulting mixture was stirred at rt for 1 hour, then concentrated. The residue was dissolved in methanol and basified with aq. saturated sodium carbonate. Flash C-18 chromatography using acetonitrile in water (0-50 %) followed by concentration of the appropriate fraction gave the title compound as a colourless oil (190 mg, 70 %):1H NMR (300 MHz, DMSO, 22°C) δ 0.68 (3H, d), 0.85 (2H, d), 1.1–1.25 (1H, m), 2.45 (3H, s), 7.6–8.07 (2H, m), 8.25 (1H, s), 8.44 (1H, d), 8.60 (1H, d).

[1539] Intermediate 55. l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutan-l-aminium chloride

[1540]

[1541] Step 1: tert-butyl (1-{[(1, 3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]carbonyl}-3-methoxycyclobutyl)carbamate

[1542]

[1543] / V-(3-Dimethylaminopropyl)- / V'-ethylcarbodiimide hydrochloride (646 mg, 3.37 mmol) was added to 4-(Dimethylamino)pyridine (56.2 mg, 0.46 mmol), diisopropylethyl amine (1.606 mL, 9.20 mmol), l-[(tert-butoxycarbonyl)amino]-3-methoxycyclobutane-l-carboxylic acid

[1544] (865 mg, 3.52 mmol, CAS RN 1700442-25-6) and 2-hydroxy-lH-isoindole-l,3(2H)-dione (500 mg, 3.07 mmol) in DCM (10 mL). The resulting mixture was stirred at rt for 2 hours. The reaction mixture was then diluted with dichloromethane (30 mL), and washed successively with aq. 0.5M citric acid (3 x 30 mL), aq. Saturated sodium hydrogen carbonate (1 x 30 mL), water (1 x 30 mL), then dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-70 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (580 mg, 48.5 %):1H NMR (400 MHz, DMSO, 21°C) δ 1.39–1.44 (9H, m), 2.22 (1H, dd), 2.43–2.48 (1H, m), 2.63–2.69 (1H, m), 2.92–3.02 (1H, m), 3.16 (3H, s), 4.02 (1H, dd), 7.93–8 (4H, m).

[1545] Step 2: tert-butyl [l-(6-chloro-5-methylpyridin-3-yl)-3-methoxycyclobutyl]carbamate

[1546]

[1547] To a stirred mixture of tert-butyl (l-{[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]carbonyl}-3-methoxycyclobutyl)carbamate (478 mg, 1.23 mmol), 5-bromo-2-chloro-3-methylpyridine (220 mg, 1.07 mmol), zinc (697 mg, 10.66 mmol), nickel chloride, dimethoxyethane adduct (46.8 mg, 0.21 mmol), 5-methoxypicolinimidamide hydrochloride (40.0 mg, 0.21 mmol) and tetrabutylammonium iodide (394 mg, 1.07 mmol) was added dimethylformamide (3 mL) at rt under nitrogen, followed by a freshly prepared solution of TFA (0.041 mL, 0.53 mmol) in dimethylformamide (0.2 mL). The mixture was stirred at rt for 2 h under nitrogen, then filtered through a pad of celite and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (50 mg, 14 %):1H NMR (400 MHz, DMSO, 20°C) 6 1.33 (9H, d), 2.22 (2H, d), 2.33 (3H, d), 2.77-2.85 (2H, m), 3.14 (3H, d), 7.77 (1H, d), 7.90 (1H, s), 8.18 (1H, d).

[1548] Step 3: tert-butyl (l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutyl)carbamate

[1549]

[1550] Prepared similar as described in step 1, intermediate 35 from l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (197 mg, 0.81 mmol, CAS RN 1206640-82-5) and tert-butyl [l-(6-chloro-5-methylpyridin-3-yl)-3-methoxycyclobutyl]carbamate (220 mg, 0.67 mmol). This was combined with a parallel batch starting from tert-butyl [l-(6-chloro-5-methylpyridin-3-yl)-3-methoxycyclobutyl]carbamate (60 mg, 0.18 mmol). Yellow solid (150 mg, 43 %):1H NMR (400 MHz,DMSO, 22°C) 61.11-1.4 (9H, m), 2.24 (2H, d), 2.47 (3H, d), 2.83 (2H, s), 3.15 (3H, d), 3.81 (1H, s), 7.65 (1H, d), 7.87 (2H, t), 8.26 (1H, d), 8.46 (1H, s), 8.63 (1H, s).

[1551] Step 4: l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutan-l-aminium chloride (intermediate 55)

[1552] tert-butyl (l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutyl)carbamate (100 mg, 0.24 mmol) was added to 4 M hydrochloric acid in dioxane (2 mL) and stirred at rt for 30 minutes, then concentrated and used in the next step without further purification (80 mg).

[1553] Intermediate 56. (5 / ?*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1554]

[1555] (N^N'H

[1556] Step 1: ethyl (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (isomer 1) and ethyl (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (isomer

[1557]

[1558] Prepared similar as described for intermediate 1 steps 1-3 from ethyl 4-(2-fluorophenyl)-4-oxobutanoate (CAS RN 898753-32-7) followed by resolution using chiral chromatography similar as described providing first ethyl (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (isomer 1) as a white solid (100 mg):1H NMR (300 MHz, DMSO, 24°C) δ 1.27 (3H, t), 2.62 (1H, ddt), 3.15 (3H, dtd), 4.28 (2H, qq), 5.80 (1H, dd), 7.2–7.33 (3H, m), 7.46 (1H, ddt), followed by ethyl (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (isomer 2) as a white solid (100 mg):1H NMR (300 MHz, DMSO, 24°C) 61.27 (3H, t), 2.62 (1H, ddt), 3.15 (3H, dtd), 4.28 (2H, qq), 5.80 (1H, dd), 7.18-7.34 (3H, m), 7.46 (1H, ddd).

[1559] Step 2: (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (intermediate 56)

[1560] ethyl (5R*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (isomer 2) (100 mg, 0.36 mmol) and lithium hydroxide (44 mg, 1.8 mmol) was stirred in 3:1 tetrahydrofurane-water at rt for 1 h, then acidified with aq. 2 M HCI and concentrated. Flash C-18 chromatography of the residueusing acetonitrile in water (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (80 mg, 89 %):1H NMR (300 MHz, DMSO, 22°C) δ 2.60 (1H, ddd), 3.04 (2H, td), 3.20 (1H, td), 5.78 (1H, dd), 7.14–7.33 (3H, m), 7.37–7.52 (1H, m).

[1561] Intermediate 57. (5 / ?*)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1562]

[1563] Prepared similar as described in step 2, intermediate 56 from ethyl (5R*)-5-(2-fluorophenyl)-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (isomer 1).

[1564] Intermediate 58. (5 / ?*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid

[1565]

[1566] Step 1: (5RS)-5-(3-fluorophenyl)pyrrolidin-2-one

[1567]

[1568] (3-Fluorophenyl)magnesium bromide (81 mL, 80.74 mmol) was added to pyrrolidine-2, 5-dione (4 g, 40.37 mmol) in dichloromethane (20 mL) at -78°C over a period of 5 minutes under nitrogen. The resulting mixture was stirred at rt for 16 h, then sodium cyanoborohydride (3.04 g, 48.44 mmol) was added to the mixture and stirred at rt another 1 h. The pH was then adjusted to 3-4 by the addition aq. 6 M HCI (16.15 mL, 96.88 mmol). After 1 hour the mixture was neutralized with sodium hydroxide in 5:1 ethanol-water. The reaction mixture was then diluted with dichloromethane (100 mL), washed with water (3 x 75 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-60 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (4.6 g, 64 %):1H NMR (300 MHz, DMSO, 23°C) 6 1.68-1.82 (1H, m), 2.19-2.28 (2H, m), 2.42-2.5 (1H, m), 4.70 (1H, t), 7.05-7.18 (3H, m), 7.35-7.47 (1H, m), 8.14 (1H, s).

[1569] Step 2: (5RS)-l-amino-5-(3-fluorophenyl)pyrrolidin-2-one

[1570]

[1571] Sodium hydride (0.924 g, 38.51 mmol) was added to (5RS)-5-(3-fluorophenyl)pyrrolidin-2-one (4.6 g, 25.67 mmol) in dimethylformamide (10 mL) at 0 °C under nitrogen and stirred for 30 min. Then, O-Diphenylphosphinylhydroxylamine (8.98 g, 38.51 mmol, CAS RN 72804-96-7) was added to the mixture at 0 °C under nitrogen. The resulting mixture was stirred at rt for 4 h, then filtered through celite and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (3.6 g, 72 %):1H NMR (300 MHz, DMSO, 23°C) 6 1.59-1.74 (1H, m), 2.21-2.44 (3H, m), 4.44 (2H, s), 4.61 (1H, t), 7.03-7.17 (3H, m), 7.41 (1H, td).

[1572] Step 3: ethyl {[(2RS)-2-(3-fluorophenyl)-5-oxopyrrolidin-l-yl]amino}(imino)acetate

[1573]

[1574] Ethyl 2-ethoxy-2-iminoacetate (21.53 g, 148.3 mmol) was added to (5RS)-l-amino-5-(3-fluorophenyl)pyrrolidin-2-one (3.6 g, 18.54 mmol) in ethanol (40 mL). The resulting mixture was stirred at 70 °C for 16 hours, then concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (5.20 g, 96 %):1H NMR (300 MHz, DMSO, 24°C) δ 1.19 (3H, q), 1.69–1.84 (1H, m), 2.3–2.47 (3H, m), 4.06–4.26 (2H, m), 4.83 (1H, t), 6.96 (2H, s), 7.07 (1H, td), 7.14–7.24 (2H, m), 7.36 (1H, td).

[1575] Step 4: ethyl (5RS)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate

[1576]

[1577] ethyl {[(2RS)-2-(3-fluorophenyl)-5-oxopyrrolidin-l-yl]amino}(imino)acetate (5.2 g, 17.73 mmol) was added to phosphoryl chloride (35 mL) and the resulting mixture was stirred at 100 °C for 3 h, then allowed to cool to rt and carefully quenched with ice-water (25 mL). The mixture was then extracted into ethyl acetate (3 x 50 mL) and the combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethanol in dichlorormethane (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (4.2 g, 86 %).

[1578] Step 5: ethyl (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 1 and ethyl (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 2.

[1579]

[1580] Preparative chiral SFC-HPLC (Column: CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: isocratic 20% B; RTl(min): 7; RT2(min): 11; Sample Solvent: EtOH; Injection Volume: 3 mL; Number Of Runs: 10) of ethyl (5RS)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (4.2 g, 15.3 mmol) followed by concentration of theappropriate fractions gave first ethyl (5 / ?*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 1 (2.0 g, 48 %):1H NMR (400 MHz, DMSO, 22°C) 6 1.22-1.31 (3H, m), 2.53-2.62 (1H, m), 2.93-3.04 (1H, m), 3.06-3.23 (2H, m), 4.23-4.34 (2H, m), 5.61 (1H, dd), 7.08-7.26 (3H, m), 7.45 (1H, td) followed by ethyl (5 / ?*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 2 (1.8 g, 43 %):TH NMR (300 MHz, DMSO, 23°C) 6 1.27 (3H, t), 2.58 (1H, ddd), 2.94-3.25 (3H, m), 4.29 (2H, qq), 5.58-5.67 (1H, m), 7.08-7.25 (3H, m), 7.46 (1H, td).

[1581] Step 6: (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (intermediate 58).

[1582] Lithium hydroxide (0.157 g, 6.54 mmol) was added to ethyl (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 2 (1.8 g, 6.54 mmol) in 1:1 ethanol-water (30 mL), then stirred at rt for 1 h. The reaction mixture was then acidified with aq. 0.1 M HCI. Flash C-18 chromatography of the residue using acetonitrile in water (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (1.30 g, 80 %):1H NMR (300 MHz, DMSO, 23°C) δ 2.53–2.63 (1H, m), 2.92–3.26 (3H, m), 5.56–5.66 (1H, m), 7.07–7.26 (3H, m), 7.46 (1H, td), 13.21 (1H, s).

[1583] Intermediate 59. (5 / ?*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid.

[1584]

[1585] Prepared similar as described in step 6, intermediate 58 from ethyl (5R*)-5-(3-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 1 (2.0 g, 7.27 mmol). White solid (1.4 g, 78 %):1H NMR (300 MHz, DMSO, 23°C) δ 2.53–2.63 (1H, m), 2.91–3.26 (3H, m), 5.55–5.65 (1H, m), 7.07–7.26 (3H, m), 7.46 (1H, td), 13.21 (1H, s).

[1586] Intermediate 60. (5 / ?*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid.

[1587]

[1588] Step 1: ethyl (5RS)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate

[1589]

[1590] Tetrakis(triphenylphosphine)palladium(0) (309 mg, 0.27 mmol) was added to zinc cyanide (2515 mg, 21.42 mmol) and ethyl (5RS)-5-(3-bromophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (900 mg, 2.68 mmol, prepared similar as described in steps 1-3 for intermediate 1 from ethyl 4-(3-bromophenyl)-4-oxobutanoate, CAS RN 147374-04-7) in dimethylformamide (10 mL) at 25°C under nitrogen. The resulting mixture was stirred at 130 °C for 3 hours, then allowed to cool to rt and diluted with water (75 mL), then extracted into ethyl acetate (3 x 100 mL). The organic layers were combined, dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.05 % formic acid (0-60 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (600 mg).

[1591] Step 2: ethyl (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 1 and ethyl (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 2.

[1592]

[1593] Preparative chiral SFC-HPLC (CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA; Flow rate: 100 mL / min; Gradient: isocratic 50% B; RTl(min): 4; RT2(min): 6; Sample Solvent: ACN;

[1594] Injection Volume: 4.9 mL) of ethyl (5RS)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate (600 mg, 2.13 mmol) followed by concentration of the appropriate fractions gave first ethyl (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 1 as a yellow oil (244 mg, 41 %):1H NMR (300 MHz, DMSO) δ 1.27 (3H, t), 2.55–2.66 (1H, m), 2.93–3.27 (3H, m), 4.29 (2H, qd), 5.67 (1H, dd), 7.56–7.69 (2H, m), 7.79–7.91 (2H, m) followed by ethyl (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate isomer 2 as a yellow oil (242 mg, 4

[1595]

[1596] 0 %): NMR (300 MHz, DMSO) 6 1.27 (3H, t), 2.55-2.66 (1H, m), 2.93-3.27 (3H, m), 4.29 (2H, qd), 5.67 (1H, dd), 7.56-7.69 (2H, m), 7.79-7.91 (2H, m).

[1597] Step 3: (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid (intermediate 60).

[1598] Prepared similar as described in step 2, intermediate 56 from ethyl (5R*)-5-(3-cyanophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylate isomer 2 (110 mg, 0.39 mmol). White solid (90 mg, 91 %):1H NMR (300 MHz, DMSO, 21°C) δ 2.53–2.62 (m, 1H), 2.87–3.2 (m, 2H), 5.64 (dd, J = 8.5, 6.1 Hz, 1H), 7.52–7.67 (m, 1H), 7.74–7.94 (m, 1H).

[1599] Intermediate 61. 3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-amine

[1600]

[1601] Step 1: 3-(5-bromo-6-methylpyridin-2-yl)oxetane-3-carbonitrile

[1602]

[1603] To a solution of oxetane-3-carbonitrile (2.19 g, 26.3 mmol) and 3-bromo-6-fluoro-2-methylpyridine (5.0 g, 26.3 mmol) in tetrahydrofurane (60 mL) cooled to -20 °C was added

[1604] sodium bis(trimethylsilyl)amide (4.83 g, 26.3 mmol) over a period of 5 minutes under nitrogen. The resulting mixture was stirred at -20 °C for 2 h, then diluted with ethyl acetate (75 ml), washed with aq. saturated ammonium chloride (3 x 50 ml), dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in pentane (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (5.0 g, 75 %):1H NMR (300 MHz, DMSO, 22°C) 62.64 (3H, s), 5.00 (2H, d), 5.10 (2H, d), 7.49 (1H, d), 8.16 (1H, d).

[1605] Step 2: sodium 3-(5-bromo-6-methylpyridin-2-yl)oxetane-3-carboxylate

[1606] e0

[1607] <rA A r

[1608] N

[1609]

[1610] oz

[1611] Sodium hydroxide (4.11 g, 102.7 mmol) was added to 3-(5-bromo-6-methylpyridin-2-yl)oxetane-3- carbonitrile (6.5 g, 25.7 mmol) in 2:1 ethanol-water (75 mL). The resulting mixture was stirred at 80 °C for 2 hours, then partly concentrated to remove ethanol.

[1612] The mixture was cooled to 0 °C and carefully neutralized with aq. IM hydrochloric acid (product sensitive to acid). Flash C-18 chromatography of the crude using acetonitrile in water (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (6.6 g, 87 %):1H NMR (500 MHz, DMSO) 62.55 (3H, s), 4.79 (2H, d), 4.95 (2H, d), 7.08 (1H, d), 7.85 (1H, d).

[1613] Step 3: tert-butyl [3-(5-bromo-6-methylpyridin-2-yl)oxetan-3-yl]carbamate

[1614]

[1615] Diphenyl phosphoryl azide (5.31 mL, 24.50 mmol) was added to sodium 3-(5-bromo-6-methylpyridin-2- yl)oxetane-3-carboxylate (6.55 g, 22.3 mmol) and triethylamine (4.04 mL, 28.95 mmol) in 1:1 toluene - 1- butanol (70 mL) and the resulting mixture was stirred at 90 °C for 15 h, then filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (5.2 g, 68 %):1H NMR (500 MHz, DMSO) δ 1.39 (9H, s), 2.63 (3H, s), 4.67 (2H, d), 4.86 (2H, d), 7.14 (1H, d), 8.01 (1H, d), 8.21 (1H, s).Step 4: tert-butyl (3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)carbamate

[1616]

[1617] [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.714 g, 0.87 mmol) was added to tert-butyl [3-(5-bromo-6-methylpyridin-2-yl)oxetan-3-yl]carbamate (3 g, 8.74 mmol), l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.346 g, 9.61 mmol, CAS RN 1206640-82-5) and potassium carbonate (2.42 g, 17.5 mmol) in dioxane (35 mL) and water (7 mL), then heated to 90 °C for 2 h under nitrogen. The reaction mixture was then allowed to cool to rt and diluted with ethyl acetate (300 mL), washed with water (2 x 100 mL) and brine (1 X 100 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-30 %) followed by concentration of the appropriate fractions gave the title compound as a pale yellow solid (3.3 g, 99 %):1H NMR (500 MHz, DMSO) 6 1.12-1.43 (9H, m), 2.64 (3H, s), 4.70 (2H, d), 4.92 (2H, d), 7.26 (1H, d), 7.74-8.01 (2H, m), 8.14 (1H, s), 8.19 (1H, s), 8.57 (1H, s).

[1618] Step 5: 3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-amine (intermediate 61)

[1619] Trifluoroacetic acid (8 mL, 8.62 mmol) was added slowly to tert-butyl (3-{5-[l-(difluoromethyl)-lH- pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)carbamate (3.28 g, 8.62 mmol) in dichloromethane (24 mL). The resulting mixture was stirred at rt for 1 hour, then concentrated. The residue was dissolved with methanol and pH was adjusted to ~8 with sodium carbonate, then filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.1 % ammonium bicarbonate (0-36 %) followed by concentration of the appropriate fractions gave the title compound as a pale yellow solid (1.80 g, 74 %):1H NMR (500 MHz, DMSO) δ 2.62 (3H, s), 2.74 (2H, s), 4.57 (2H, d), 4.90 (2H, d), 7.55 (1H, d), 7.74–8 (2H, m), 8.15 (1H, s), 8.57 (1H, d).

[1620] Intermediate 62. 3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-amine

[1621]

[1622] Step 1: / V-[3-(5-chloro-6-methylpyrazin-2-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide

[1623]

[1624] o

[1625] 2.5 M butyllithium in hexanes (9.64 mL, 24.10 mmol) was added dropwise to 5-bromo-2-chloro-3- methylpyrazine (5.0 g, 24.1 mmol) in tetrahydrofurane (30 mL) at -78 °C under nitrogen, and stirred for 30 mins, then 2-methyl- / V-(oxetan-3-ylidene)propane-2-sulfinamide (4.2 g, 24.1 mmol, CAS RN 1158098-73-7) in tetrahydrofurane (4 mL) was added dropwise and the reaction mixture was kept at -78 °C for additional 30 min, then stirred at rt for 1 h. The reaction mixture was then carefully quenched with ice water (50 mL) and extracted into ethyl acetate (2 x 50 mL). The combined organic layers were then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (2.1 g, 29 %): 1H NMR (300 MHz, DMSO, 23°C) 6 1.15 (9H, s), 2.64 (3H, d), 4.82 (1H, d), 4.92 (2H, d), 5.06 (1H, d), 6.58 (1H, s), 8.50 (1H, d).

[1626] Step 2: / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-2-methylpropane- 2-sulfinamide

[1627]

[1628] [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.538 g, 0.66 mmol) was added to a potassium carbonate (1.14 g, 8.2 mmol), / V-[3-(5-chloro-6-methylpyrazin-2-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (1 g, 3.29 mmol) and l-(difluoromethyl)-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.88 g, 3.62 mmol, CAS RN 1206640-82-5) in 1,4-dioxane (9 mL) and water (3 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 2 hours. Then allowed to cool to rt and filtered through celite and concentrated. The crude was combined with a parallel batch starting from / V-[3-(5-chloro-6-methylpyrazin-2-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (0.55 g, 1.81 mmol). Flash C-18 chromatography of the residues using acetonitrile in water (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a brown gum (1.3 g, 66 %):1H NMR (400 MHz, DMSO, 23°C) 6 1.17 (9H, s), 2.77 (3H, s), 4.86 (1H, d), 4.93-4.99 (2H, m), 5.16 (1H, d), 6.60 (1H, s), 7.91 (1H, t), 8.37 (1H, s), 8.69 (1H, s), 8.81 (1H, s).

[1629] Step 3: 3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-amine (intermediate 62).

[1630] l,3-dibromo-5,5-dimethylimidazolidine-2, 4-dione (1.45 g, 5.06 mmol) was added to / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide (1.3 g, 3.37 mmol) in THF (25 mL) under nitrogen. The resulting mixture was stirred at rt for 2 hours, then work up similar as described in step 3, intermediate 43. The residue was combined with a parallel batch starting from l g, 2.59 mmol / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide (1.3 g, 3.37 mmol). ). Flash C-18 chromatography of the residues using acetonitrile in water (0-25 %) followed by concentration of the appropriate fractions gave the title compound as a brown solid:1H NMR (400 MHz, DMSO, 22°C) 62.50 (3H, d), 4.2-4.31 (1H, m), 6.65-6.94 (1H, m), 7.49 (1H, dd), 7.76-7.84 (1H, m), 7.98-8.07 (1H, m).Intermediate 63. (5S)- / V-[3-(4-bromo-3-methylphenyl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1631]

[1632] Prepared similar as described for intermediate 3 from intermediate 1 (300 mg, 1.31 mmol) and 3-(4- bromo-3-methylphenyl)oxetan-3-amine (380 mg, 1.57 mmol, CAS RN 2384894-49-7). m / z (ES+) [M+H]+ = 453.

[1633] Intermediate 64. 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-amine

[1634]

[1635] Step 1: / V-[3-(6-chloropyridin-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide

[1636]

[1637] o

[1638] Prepared similar as described in step 1, intermediate 62 from 5-bromo-2-chloropyridine (900 mg, 4.68 mmol). The residue was purified by first flash chromatography using methanol in dichloromethane (0-8 %). Appropriate fractions were concentrated and the residue was further purified by flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-33 %). Appropriate fractions were concentrated to provide the title compound as a yellow gum (750 mg, 55 %):1H NMR (500 MHz, DMSO) 6 1.13 (9H, s), 4.78 (1H, d), 4.90 (1H, d), 4.98 (2H, dd), 6.48 (1H, s), 7.58 (1H, d), 7.98 (1H, dd), 8.57 (1H, d).

[1639] Step 2: / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-2-methylpropane-2- sulfinamide

[1640]

[1641] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (68 mg, 0.08 mmol) was added to / V-[3-(6-chloropyridin-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (240 mg, 0.83 mmol), l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (243 mg, 1.0 mmol, CAS RN 1206640-82-5) in dioxane (5 mL) and water (1 mL). The resulting mixture was stirred at 90 °C for 2 hours under nitrogen, then allowed to reach rt, filtered through celite and concentrated. Flash C- 18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-33 %) followed by concentration of the appropriate fractions gave the title compound as an off-white gum (250 mg, 81 %):1H NMR (500 MHz, DMSO) 6 1.13 (9H, s), 4.80 (1H, d), 4.93 (1H, d), 5.04 (2H, d), 6.46 (1H, s), 7.75-8.01 (3H, m), 8.39 (1H, s), 8.70 (1H, dd), 8.86 (1H, s).

[1642] Step 3: 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-amine (intermediate 64) Prepared similar as described in step 3, intermediate 43 and used directly in the next step.

[1643] Intermediate 65. 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}- / V-methyloxetan-3-amine

[1644]

[1645] Step 1: / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]- / \ / ,2-dimethylpropane-2-sulfinamide

[1646]

[1647] Sodium hydride (52 mg, 1.30 mmol) was added slowly to / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (300 mg, 0.86 mmol, prepared as described in step 1, intermediate 43) in dimethylformamide (6 mL) at 0 °C. Then methyl iodide (184 mg, 1.30 mmol) was added and the reaction mixture was stirred at rt for 2 h, then quenched with water (50 mL). The mixture was extracted with ethyl acetate (1 x 100 mL) and the organic layer was dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (240 mg, 77 %):1H NMR (500 MHz, DMSO) 6 1.22 (9H, s), 2.30 (3H, s), 2.37 (3H, s), 4.77-4.99 (4H, m), 7.90 (lH, d), 8.34 (lH, d).

[1648] Step 2: / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)- / V,2-dimethylpropane-2-sulfinamide

[1649]

[1650] l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (40 mg, 0.06 mmol) was added to / V-[3-(6-bromo-5-methylpyridin-3-yl)oxetan-3-yl]- / V,2-dimethylpropane-2-sulfinamide (220 mg, 0.61 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (223 mg, 0.91 mmol, CAS RN 1206640-82-5) and potassium carbonate (252 mg, 1.83 mmol) in dioxane (4 mL) and water (1 mL) under nitrogen. The resulting mixture was stirred at 50 °C for 2 hours, then allowed to cool to rt and filtered through celite and concentrated. Flash C-18 chromatography using acetonitrile in water with 0.1% ammonium bicarbonate (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (230 mg, 95 %):1H NMR (300 MHz, DMSO, 23°C) 61.24 (9H, s), 2.33 (9H, s),2.51 (3H, d), 4.72-5.15 (4H, m), 7.83 (1H, d), 7.87-8.19 (1H, m), 8.32 (1H, s), 8.58 (1H, d), 8.70 (1H, d).

[1651] Step 3: 3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}- / V-methyloxetan-3-amine (intermediate 65)

[1652] Prepared similar as described in step 3, intermediate 43 from / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)- / V,2-dimethylpropane-2-sulfinamide (210 mg, 0.53 mmol). Flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-100 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (60 mg, 39 %):1H NMR (500 MHz, DMSO) 6 2.04 (3H, s), 2.49 (3H, s), 2.97 (1H, s), 4.68 (2H, d), 4.77 (2H, d), 7.74 (1H, d), 7.87 (1H, t), 8.29 (1H, s), 8.52 (1H, d), 8.65 (1H, s).

[1653] Intermediate 66. (5S)-5-phenyl- / V-[l-(lH-pyrazol-4-yl)cyclopropyl]-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxamide

[1654]

[1655] Step 1: l-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)cyclopropan-l-amine

[1656]

[1657] Titanium(IV) isopropoxide (3.64 mL, 12.31 mmol) was added dropwise to l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-4-carbonitrile (2.5 g, 11.2 mmol, CAS RN 1822786-64-0) in diethyl ether (50 mL) at -78°C under nitrogen, then stirred for 15 min. To the resulting reaction mixture was added 3 M ethylmagnesium bromide in diethyl ether (8.2 mL, 24.6 mmol), then allowed to react rt and stirred for 1 h. Then, trifluoroborane in diethyl ether (2.6 mL, 22.4 mmol) was added and the reaction mixture was stirred at rt for 30 min. The reaction mixture was then poured into aq. saturated sodium bicarbonate (125 mL), extracted with ethyl acetate (3 x 200 ml) and the comined organic layers were dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a pale yellow liquid (0.21 g, 7 %): 1H NMR (500 MHz, DMSO) 60.01 (9H, s), 0.70 (2H, q), 0.8-0.85 (4H, m), 2.25 (2H, s), 3.46-3.53 (2H, m), 5.29 (2H, s), 7.31 (1H, d), 7.62 (1H, d).Step 2: (5S)-5-phenyl- / V-[l-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)cyclopropyl]-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1658]

[1659] Prepared similar as described in example 82 from l-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)cyclopropan-l-amine (150 mg, 0.59 mmol) and intermediate 1 (123 mg, 0.54 mmol). Flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-50 %) followed by concentration of the appropriate fractions gave the title compound as yellow solid (180 mg, 72 %): 1H NMR (500 MHz, DMSO) 6 -0.06 (9H, s), 0.76-0.83 (2H, m), 0.97-1.05 (2H, m), 1.11 (2H, td), 2.51-2.58 (1H, m), 2.97 (1H, ddd), 3.09 (1H, ddd), 3.13-3.21 (1H, m), 3.45-3.51 (2H, m), 5.28 (2H, s), 5.55 (1H, dd), 7.21-7.27 (2H, m), 7.29 (1H, d), 7.32-7.43 (3H, m), 7.60 (1H, d), 9.01 (1H, s).

[1660] Step 3: (5S)-5-phenyl- / V-[l-(lH-pyrazol-4-yl)cyclopropyl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (intermediate 66)

[1661] Trifluoroacetic acid (0.5 ml, 6.49 mmol) was added to (5S)-5-phenyl- / V-[l-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)cyclopropyl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (175 mg, 0.38 mmol) in dichloromethane (1.5 mL). The resulting mixture was stirred at RT for 2 h, then concentrated. The residue was dissloved in acetonitrile and adjusted to pH 8 with aq. saturated sodium carbonate. Flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-50 %) followed by concentration of the appropriate fractions gave the title compound as white solid (120 mg, 95 %): 1H NMR (500 MHz, DMSO) δ 0.95–1.02 (2H, m), 1.10 (2H, dp), 2.51-2.59 (1H, m), 2.97 (1H, ddd), 3.04-3.12 (1H, m), 3.14-3.22 (1H, m), 5.54 (1H, dd), 7.13-7.54 (7H, m), 8.98 (1H, d), 12.49 (1H, s).

[1662] Intermediate 67. di-tert-butyl (7-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)-2-imidodicarbonate

[1663]

[1664] A solution of di-tert-butyl dicarbonate (1.54 g, 7.04 mmol) in dichloromethane (1.2 mL) was added to a stirred mixture of 7-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine

[1665] (0.50 g, 2.35 mmol) and N, N-dimethylpyridin-4-amine (0.14 g, 1.17 mmol) in dichloromethane (6 mL) at ice-water bath. The resulting mixture was stirred at rt for 2 h, then diluted with dichloromethane (100 mL) and washed successively with water (1 x 25 mL) and brine (1 x 25 mL), then dried (sodium sulphate),filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.70 g, 72 %): 1H NMR (300 MHz, DMSO, 23°C) 6 1.41 (18H, s), 7.48 (1H, dd), 8.27 (1H, dd), 8.96 (1H, dd).

[1666] Intermediate 68. (5S)-5-phenyl- / V-[3-(lH-pyrazol-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazole-2-carboxamide

[1667]

[1668] Step 1: 3-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)oxetan-3-ol

[1669]

[1670] n-Butyllithium, 2.5M solution in hexanes (0.99 g, 15.5 mmol) was added to 4-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (4.3 g, 15.5 mmol, CAS RN 133560-58-4) in tetrahydrofurane (50 mL) at 0 °C under nitrogen. The resulting mixture was stirred at rt for 30 minutes. Then, oxetan-3-one (6.2 mL, 15.5 mmol) was added at 0 °C, then allowed to reach rt and stirred for 2 h. The reaction mixture was then quenched with water (100 mL), extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using methanol in dichloromethane (0-3 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (2.8 g, 67 %):1H NMR (500 MHz, DMSO) 6 -0.05 (9H, s), 0.82 (2H, t), 3.53 (2H, t), 4.60 (2H, d), 4.68 (2H, d), 5.37 (2H, s), 6.15 (1H, s), 7.59 (1H, s), 7.90 (1H, s).

[1671] Step 2: 4-(3-azidooxetan-3-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole

[1672]

[1673] l,8-Diazabicyclo[5.4.0]undec-7-ene (1.55 g, 10.2 mmol) was added to Diphenyl phosphoryl azide (2.80 g, 10.2 mmol) and 3-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)oxetan-3-ol (2.5 g, 9.25 mmol) in toluene (30 mL) at 0 °C. The resulting mixture was stirred at 80 °C for 2 h, then concentrated. Flash C-18 chromatography using acetonitrile in water (0-60 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (2.60 g, 95 %):1H NMR (300 MHz, DMSO, 23°C) 6 -0.05 (9H, s), 0.78-0.86 (2H, m), 3.5-3.56 (2H, m), 4.77-4.86 (4H, m), 5.42 (2H, s), 7.74 (1H, d), 8.19 (1H, d).

[1674] Step 3: 3-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)oxetan-3-amine

[1675]

[1676] 1 M trimethylphosphine solution in tetrahydrofurane (11.8 mL, 11.8 mmol) was added dropwise to 4-(3-azidooxetan-3-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (2.9 g, 9.82 mmol) in tetrahydrofurane (30 mL) and water (10 mL). The resulting mixture was stirred at rt for 20 min, then concentrated. Flash C-18 chromatography using acetonitrile in water (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (2.1 g, 79 %): 1H NMR (300 MHz, DMSO, 24°C) 6 -0.05 (9H, s), 0.79-0.86 (2H, m), 3.49-3.57 (2H, m), 4.56 (4H, d), 5.37 (2H, s), 7.62 (1H, d), 7.91 (1H, d).

[1677] Step 4: (5S)-5-phenyl- / V-[3-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1678]

[1679] Prepared similar as described in example 82 from 3-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)oxetan-3-amine (1.175 g, 4.36 mmol) and intermediate 1 (1.0 g, 4.36 mmol). Flash C-18 chromatography using acetonitrile in water (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (1.40 g, 67 %):1H NMR (500 MHz, DMSO) 6 -0.06 (9H, s), 0.78-0.83 (2H, m), 2.56 (1H, ddt), 2.99 (1H, ddd), 3.07-3.14 (1H, m), 3.20 (1H, dddd), 3.49-3.55 (2H, m), 4.64 (2H, t), 4.91 (2H, dd), 5.35 (2H, s), 5.57 (1H, dd), 7.24–7.27 (2H, m), 7.34-7.42 (3H, m), 7.54 (1H, d), 7.85 (1H, d), 9.49 (1H, s).

[1680] Step 5: (5S)-5-phenyl- / V-[3-(lH-pyrazol-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (intermediate 68)

[1681] 1 M Tetrabutylammonium fluoride solution in tetrahydrofurane (3.50 mL, 3.50 mmol) was added to (5S)-5-phenyl- / V-[3-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (1.4 g, 2.91 mmol) in THF (15 mL). The resulting mixture was stirred at 60 °C for 16 hours. 800 mg of the crude product was purified by preparative SFC (Column: Lux 5um Cellulose-4,3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: methanol; Flow rate: 90 mL / min; Gradient: isocratic 50% B; Wave Length: 220 nm; RTl(min): 5.9; RT2(min): 7) followed by concentration of appropriate fractions gave first the title compound as a white solid (620 mg, 78 %):1H NMR (400 MHz, DMSO, 21°C) 6 2.56 (1H, ddd), 2.99 (1H, ddd), 3.06-3.25 (2H, m), 4.65 (2H, dd), 4.91 (2H, dd), 5.56 (1H, dd), 7.22-7.28 (2H, m), 7.33-7.43 (3H, m), 7.59 (2H, d), 9.46 (1H, d), 12.71 (1H, s), followed by (5R)-5-phenyl- / V-[3-(lH-pyrazol-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide as a white solid (40 mg):1H NMR (400 MHz, DMSO, 21°C) 6 2.53–2.6 (1H, m), 2.99 (1H, ddd), 3.07-3.23 (2H, m), 4.65 (2H, t), 4.90 (2H, dd), 5.56 (1H, dd), 7.22-7.28 (2H, m), 7.39 (3H, dddd), 7.45-7.73 (2H, m), 9.46 (1H, s), 12.70 (1H, s).

[1682] Intermediate 69. 7-bromo-2-(difluoromethyl)[l,2,4]triazolo[l,5-a]pyridine

[1683]

[1684] Step 1: (7-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)methanol

[1685]

[1686] Sodium borohydride (1.6 g, 42.2 mmol) was added to ethyl ethyl 7-bromo[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (1.9 g, 7.0 mmol) in tetrahydrofurane (10 mL). The resulting mixture was stirred at 65 °C for 15 minutes, then ethanol (10 mL) was added and the resulting mixture was stirred at 65 °C for 4 hours. The reaction mixture was quenched with aq. saturated ammonium chloride (100 mL) and extracted with dichloromethane (3 x 150 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using methanol in dichloromethane (0-10 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (1.0 g, 62 %):1H NMR (400 MHz, DMSO, 21°C) 64.63 (2H, s), 5.51 (1H, s), 7.34 (1H, dd), 8.14 (1H, d), 8.87 (1H, d).

[1687] Step 2: 7-bromo[l,2,4]triazolo[l,5-o]pyridine-2-carbaldehyde

[1688]

[1689] Dess-Martin periodinane (1.77 g, 4.17 mmol) was added to 7-bromo[l,2,4]triazolo[l,5-o]pyridin-2-yl)methanol (0.50 mg, 2.19 mmol) in dichloromethane (8 mL), then stirred at rt for 2 h. The reaction mixture was quenched with aq. sodium thiosulphate (50 mL) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with aq. saturated sodium bicarbonate, then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using methanol in dichloromethane (0-10 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (0.30 g, 60 %).

[1690] Step 3: 7-bromo-2-(difluoromethyl)[l,2,4]triazolo[l,5-a]pyridine (intermediate 69)

[1691] Diethylaminosulfur trifluoride (0.16 mL, 1.19 mmol) was added to 7-bromo[l,2,4]triazolo[l,5-o]pyridine-2-carbaldehyde (270 mg, 1.19 mmol) in dichloromethane (4 mL) at -78 °C under nitrogen. The reaction mixture was allowed to reach rt and stirred for 2 h, then aq. saturated sodium bicarbonate (15 mL) was added and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layerswere dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (58 mg, 20 %):TH NMR (300 MHz, DMSO, 23°C) 67.32 (1H, t), 7.54 (1H, dd), 8.36 (1H, dd), 9.03 (1H, dd).

[1692] Intermediate 70. l-{l-[4-(difluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}cyclopropan-l-aminium trifluoroacetate

[1693]

[1694] Step 1: l-azido-4-(difluoromethoxy)benzene

[1695] N3-0"°)_F

[1696]

[1697] Trimethylsilyl azide (434 mg, 3.77 mmol) was added to t-butylnitrite, tech. (486 mg, 4.71 mmol) and 4-(difluoromethoxy)aniline (500 mg, 3.14 mmol) in acetonitrile (7 mL), then stirred at 0 °C for 16 h and concentrated. Flash chromatography of the residue using ethyl acetate in heptane (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (240 mg, 41 %).

[1698] Step 2: tert-butyl (l-{l-[4-(difluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}cyclopropyl)carbamate

[1699]

[1700] Anhydrous cupric sulphate (207 mg, 1.30 mmol) was added to L-Ascorbic acid, sodium salt (642 mg, 3.24 mmol), l-azido-4-(difluoromethoxy)benzene (200 mg, 1.08 mmol) and tert-butyl (1-ethynylcyclopropyl)carbamate (235 mg, 1.30 mmol, CAS RN 1268810-09-8) in water (5 mL) and dioxane (5 mL), then stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate (5 mL), then washed with water (2 x 5 ml) and brine (1 x 5 mL). The organic layer was dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in heptane (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a cream solid (300 mg, 76 %):1H NMR (300 MHz, DMSO) 6 1.15 (2H, t), 1.24-1.29 (2H, m), 1.40 (9H, s), 7.07-7.62 (4H, m), 7.91-8 (2H, m), 8.41 (1H, s).

[1701] Step 3: l-{l-[4-(difluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}cyclopropan-l-aminium trifluoroacetate (intermediate 70)Trifluoroacetic acid (140 mg, 1.23 mmol) was added to tert-butyl (l-{l-[4-(difluoromethoxy)phenyl]-lH- l,2,3-triazol-4-yl}cyclopropyl)carbamate (150 mg, 0.41 mmol) in dichloromethane (5 mL) and stirred at rt for 1 h, then concentrated and used in the next step without further purification.

[1702] Intermediate 71. l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropan-l-amine

[1703]

[1704] Step 1: tert-butyl (l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropyl)carbamate

[1705]

[1706] Bis(triphenylphosphine)palladium(ll) dichloride (86 mg, 0.12 mmol) was added to tert-butyl (1-ethynylcyclopropyl)carbamate (245 mg, 1.35 mmol, CAS RN 1268810-09-8), l-(difluoromethyl)-4-iodo- lH-pyrazole (300 mg, 1.23 mmol, CAS RN 1041205-43-9), triethyl amine (0.34 mL, 2.46 mmol) and copper(l) iodide (23.4 mg, 0.12 mmol) in dioxane (5 mL). The resulting mixture was stirred at 80 °C for 2 hours under nitrogen, then allowed to cool to rt, filtered through celite and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-15 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (280 mg, 77 %):1H NMR (500 MHz, DMSO) 61.04 (2H, t), 1.12 (2H, q), 1.38 (9H, s), 7.58-7.89 (3H, m), 8.47 (1H, s).

[1707] Step 2: l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropan-l-amine (intermediate 71)

[1708] Trifluoroacetic acid (1 ml, 13 mmol) was added to tert-butyl (l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropyl)carbamate (270 mg, 0.91 mmol) in dichloromethane (3 mL). The resulting mixture was stirred at rt for 2 hours, then concentrated. The residue was dissolved in methanol and basified using sodium carbonate, then filtered and concentrated. Flash C-18 chromatography using acetonitrile in water with 0.1 % ammonium bicarbonate (0-40 %) followed by concentration of the appropriate fractions gave the title compound as a pale yellow solid (140 mg, 78 %):1H NMR (500 MHz, DMSO) 6 0.79-0.91 (4H, m), 3.17 (2H, s), 7.64-7.89 (2H, m), 8.44 (1H, d).

[1709] Intermediate 72.3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-amine

[1710]

[1711] Step 1: tert-butyl (3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-yl)carbamate

[1712]

[1713] Prepared similar as described in step 1, intermediate 71 starting from tert-butyl (3-ethynyloxetan-3-yl)carbamate (267 mg, 1.35 mmol, CAS RN 1678527-98-4) and l-(difluoromethyl)-4-iodo-lH-pyrazole (300 mg, 1.23 mmol, CAS RN 1041205-43-9). Pale yellow solid (290 mg, 75 %):1H NMR (500 MHz, DMSO) δ 1.40 (9H, s), 4.65 (2H, d), 4.68 (2H, d), 7.80 (1H, t), 7.96 (1H, s), 8.01 (1H, s), 8.57 (1H, s).

[1714] Step 2: 3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-amine (intermediate 72)

[1715] Prepared and purified similar as described in step 2, intermediate 71 starting from tert-butyl (3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-yl)carbamate (280 mg, 0.89 mmol). Yellow crystalline solid (180 mg, 94 %):1H NMR (400 MHz, DMSO, 20°C) 6 2.61 (2H, s), 4.48 (2H, d), 4.67 (2H, d), 7.65-7.97 (2H, m), 8.54 (1H, s).

[1716] Intermediate 73. l-[(2-aminopyrimidin-5-yl)ethynyl]cyclopropan-l-aminium trifluoroacetate

[1717]

[1718] Prepared similar as described in steps 1 and 2 for intermediate 71 starting from tert-butyl (3-ethynyloxetan-3-yl)carbamate (984 mg, 5.43 mmol, CAS RN 1678527-98-4) and l-(difluoromethyl)-4-iodo-lH-pyrazole (300 mg, 1.23 mmol, CAS RN 1445-39-2). N-deprotection using trifluoroacetic acid. Title compound used in the next step without further purification.

[1719] Intermediate 74. 5-[6-(3-aminooxetan-3-yl)-2-methylpyridin-3-yl]pyrimidin-2-amine

[1720]

[1721] Step 1: tert-butyl {3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}carbamate

[1722]

[1723] Prepared and purified similar as described in step 4, intermediate 61 from tert-butyl [3-(5-bromo-6-methylpyridin-2-yl)oxetan-3-yl]carbamate (150 mg, 0.44 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (106 mg, 0.48 mmol, CAS RN 402960-38-7). White solid (140 mg, 90%):1H NMR (500 MHz, DMSO, 24°C) δ 1.41 (9H, s), 2.53 (3H, s), 4.70 (2H, d), 4.92 (2H, d), 6.83 (2H, s), 7.26 (1H, d), 7.65 (1H, d), 8.21 (1H, s), 8.33 (2H, s).Step 2: 5-[6-(3-aminooxetan-3-yl)-2-methylpyridin-3-yl]pyrimidin-2-amine (intermediate 74)

[1724] Prepared similar as described in step 5, intermediate 61 from tert-butyl {3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}carbamate (140 mg, 0.39 mmol). White solid (100 mg, 99 %):1H NMR (300 MHz, DMSO, 22°C) δ 2.54 (s, 3H), 2.72 (2H, s), 4.55 (2H, d), 4.89 (2H, d), 6.80 (2H, s), 7.53 (1H, d), 7.65 (1H, d), 8.30 (2H, s).

[1725] Intermediate 75. (5S)- / V-[(l / ? S)-l-(5-bromo-6-methylpyridin-2-yl)ethyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[1726]

[1727] Prepared similar as described for intermediate 3 from (lRS)-l-(5-bromo-6-methylpyridin-2-yl)ethan-l-amine (250 mg, 0.99 mmol, CAS RN 1270484-17-7) and intermediate 1 (228 mg, 0.99 mmol). Colourless gum (330 mg, 78 %):1H NMR (300 MHz, DMSO, 24°C) δ 1.45 (3H, d), 2.58 (4H, s), 2.93-3.3 (3H, m), 5.08 (1H, p), 5.58 (1H, t), 7.16-7.3 (3H, m), 7.40 (3H, dddd), 7.92-8.04 (1H, m), 8.78 (1H, d).

[1728] Intermediate 76: (l / ? S)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethan-l-amine

[1729]

[1730] Step 1: l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethan-l-one

[1731]

[1732] [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (129 mg, 0.18 mmol) was added to l-(5-chloro-6-methylpyrazin-2-yl)ethan-l-one (300mg, 1.76 mmol, CAS RN 1783373-24-9), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (515 mg, 2.11 mmol, CAS RN 1206640-82-5) and potassium carbonate (486 mg, 3.52 mmol) in dioxane (5mL) and water (ImL) at rt under nitrogen. The resulting mixture was stirred at 80 °C for 3 hours. The reaction mixture was then diluted with ethyl acetate (50 mL), washed with water (2 x 50 mL), dried (sodium sulphate) filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-25 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (400 mg, 90 %):1H NMR (300 MHz, DMSO, 23°C) δ 2.65 (3H, s), 2.82 (3H, d), 7.93 (1H, t), 8.45 (1H, s), 8.95 (2H, dd).Step 2: / V-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl)-2-methylpropane-2-sulfinamide

[1733]

[1734] Titanium ethoxide (1085 mg, 4.76 mmol) was added to l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethan-l-one (400 mg, 1.59 mmol) and 2-methylpropane-2-sulfinamide (231 mg, 1.90 mmol) in tetrahydrofurane (7 mL) at rt under nitrogen. The resulting mixture was stirred at 80 °C for 16 hours, then allowed to cool to rt and quenched with water (15 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organi layers were dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-50 %) followed by concentration of the appropriate fractions gave a yellow solid (410 mg). The residue was combined with a parallel batch starting from l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethan-l-one (240 mg, 0.95 mmol) and was treated with sodium borohydride (179 mg, 4.73 mmol) in methanol (8 mL) at 0 °C for 1 h. The reaction mixture was then diluted with ethyl acetate (100 mL) and washed with water (1 x 100 mL) and brine (1 x 50 mL), dried (sodium sulphate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.1 % ammonium bicarbonate (0-50 %) followed by concentration of the appropriate fractions gave the title compound as a colourless gum as a 3:1 diastereomeric mixture (500 mg, 55 %):1H NMR (300 MHz, DMSO, 24°C) δ 1.14 (9H, s), 1.56 (3H, d), 2.70 (3H, s), 4.52 (1H, dt), 5.64 (1H, d), 7.91 (1H, td), 8.34 (1H, d), 8.60 (1H, s), 8.76 (1H, t).

[1735] Step 3: (lRS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethan-l-amine (intermediate 76)

[1736] To / V-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl)-2-methylpropane-2-sulfinamide (470 mg, 1.31 mmol) in dichloromethane (8 mL) was added 4 M hydrochloric acid in dioxane (4 mL) at rt, stirred for 30 min, then concentrated. The residue was dissolved in methanol and basified using sodium carbonate, then filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water with 0.1 % ammonium bicarbonate (0-10 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (300 mg, 79 %):1H NMR (300 MHz, DMSO, 24°C) δ 1.57 (3H, d), 2.71-2.8 (3H, m), 4.53-4.7 (1H, m), 7.96 (1H, t), 8.38 (1H, d), 8.58-8.83 (4H, m), 8.86 (1H, d).

[1737] Intermediate 77. l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutan-l-amine

[1738]

[1739] Step 1: tert-butyl (l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutyl)carbamate

[1740]

[1741] [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (53 mg, 0.06 mmol) was added to tert-butyl [l-(4-bromophenyl)cyclobutyl]carbamate

[1742] (210 mg, 0.64 mmol, CAS RN 1032350-06-3), l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (173 mg, 0.71 mmol, CAS RN 1206640-82-5) and potassium carbonate (178 mg, 1.29 mmol) in dioxane (4 mL) and water (0.8 mL). The resulting mixture was stirred at 90 °C for 2 hours under nitrogen, then allowed to cool to rt, diluted with ethyl acetate (50 mL), washed with water (1 x 15 mL) and brine (1 X 10 mL), then dried (sodium sulphate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (0-20 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (230 mg, 98 %): 1H NMR (500 MHz, DMSO) δ 1.08-1.42 (9H, m), 1.78 (1H, s), 1.94-2.03 (1H, m), 2.32-2.47 (4H, m), 7.37-7.42 (2H, m), 7.63 (2H, d), 7.84 (1H, td), 8.25 (1H, s), 8.68 (1H, s).

[1743] Step 2: l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutan-l-amine (example 77)

[1744] Trifluoroacetic acid (0.5 mL, 0.61 mmol) was added to tert-butyl (l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutyl)carbamate (220 mg, 0.61 mm...

Claims

1. CLAIMS1. A compound of formula (I):wherein:R1is C1-4alkyl, C1-4haloalkyl or phenyl; wherein said phenyl may be substituted by one or two R1a;each R1ais independently halo, CN, C1-4alkyl or C1-4haloalkyl;n is 0, 1 or 2;each R2is independently halo or OH;m is 1 or 2;R10is H, C1-4alkyl or C1-4haloalkyl;R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C1-4alkylene(OH); orR11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13;each R13is independently halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;A is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;B is a 3-7 membered heterocycloalkyl, 5-membered monocyclic heteroaryl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 8-10 membered bicyclic heteroaryl, each of which may be independently substituted by one or two R30;each R30is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, NR30aR30b, C(O)NR30cR30d, NR30eC(O)R30f, S(O)2NR30gR30h, NR30iS(O)2R30j, C1-4alkylene(CN), C0-4alkylene(C3-6cycloalkyl), C0-4alkylene(3-7 membered heterocycloalkyl) or C0-4alkylene(5-6 membered monocyclic heteroaryl);wherein when R30is C0-4alkylene(C3-6cycloalkyl), C0-4alkylene(3-7 membered heterocycloalkyl) or C0-4alkylene(5-6 membered monocyclic heteroaryl), said C3-6cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C(O)C1-4alkyl;wherein when B is a 3-7 membered heterocycloalkyl or 8-10 membered bicyclic heteroaryl, each R30may additionally be =0; andR30a, R30b, R30c, R30d, R30e, R30f, R30g, R30h, R30iand R30jare each independently H, Ci.4al kyl or Ci^haloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1is unsubstituted phenyl.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is 0.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein m is 1.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R10is H.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which is:wherein denotes the point of attachment to N(R10), and denotes the point of attachment to A.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein A is phenyl or a 5-6 membered monocyclic heteroaryl.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein the phenyl or 5-6 membered monocyclic heteroaryl are each independently substituted by one or two (such as one) R20, and each R20is independently CN, Cl, F, methyl, ethyl, CF3, OCF3or OCHF2.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein A is phenyl or 5-6 membered monocyclic heteroaryl (such as pyridyl, pyrimidinyl or pyridazinyl, for example pyridyl), each of which are independently substituted by one R20, and R20is CN, Cl, F, methyl, ethyl, CF3, OCF3or OCHF2.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein A is:such as:wherein denotes the point of attachment to C(R11)(R12), and denotes the point of attachment to B.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein B is a 5-membered monocyclic heteroaryl, such as pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl or thiadiazolyl, for example pyrazolyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein B is a 5-membered monocyclic heteroaryl (such as pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl or thiadiazolyl, for example pyrazolyl) substituted by one or two R30;each R30is independently CN, halo (such as F), Ci.4alkyl (such as methyl), Ci.4haloalkyl (such as CHF2), Ci-4alkoxy (such as OMe), NR30aR30b(such as NH2), Ci.4alkylene(CN) (such as CH2CN or CH2CH2CN) or Co-4alkylene(3-7 membered heterocycloalkyl) (such as oxetanyl or piperidinyl); andsaid 3-7 membered heterocycloalkyl may be substituted by one Ci.4alkyl (such as methyl) or C(O)Ci.4alkyl (such as C(O)Me).

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein B is:such as:

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein:B is pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl (such as pyrimidinyl) substituted by one or two R30; and each R30is independently CN, halo (such as F), Ci.4alkyl (such as methyl), Ci.4haloalkyl (such as CHF2), Ci.4alkoxy (such as OMe), NR30aR30b(such as NH2) or C(O)NR30cR30d(such as C(O)NH2).

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 or 15, wherein B is:

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein the carbon bearing R1has the following stereochemistry:R118. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, which is a compound of formula (IC):wherein:R1is phenyl; wherein said phenyl may be substituted by one or two Rla;each Rlais independently halo or CN;R10is H or Ci-4alkyl;R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl, each of which may be independently substituted by one or two R13; each R13is independently halo or Ci-4alkyl;A is phenyl or 6 membered monocyclic heteroaryl; wherein said phenyl or 6 membered monocyclic heteroaryl may each be independently substituted by one R20;each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy;B is pyrazolyl, imidazolyl, triazolyl, oxazolyl, iso-oxazolyl, thiazolyl, thiadiazolyl or pyrimidinyl, each of which may be independently substituted by one or two R30;each R30is independently CN, halo, Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy, NR30aR30b, Ci-4alkylene(CN) or Co-4alkylene(3-7 membered heterocycloalkyl);wherein when R30is Co-4alkylene(3-7 membered heterocycloalkyl), said 3-7 membered heterocycloalkyl may be independently substituted by one Ci-4alkyl, Ci.4haloalkyl, Ci.4alkoxy, Ci.4haloalkoxy or C(O)Ci.4alkyl; andR30aand R30bare each independently H, Ci.4alkyl or Ci.4haloalkyl;or a pharmaceutically acceptable salt thereof.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, which is a compound of formula (ID):wherein:R1is phenyl; wherein said phenyl may be substituted by one or two Rla;each Rlais independently halo or CN;n is 0, 1 or 2;each R2is independently halo or OH;m is 1 or 2;R10is H or Ci-4alkyl;R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; or R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which isA is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; andBisor a pharmaceutically acceptable salt thereof.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, which is a compound of formula (IE):R10M - NN <Nwherein:R1is phenyl; wherein said phenyl may be substituted by one or two Rla;each Rlais independently halo or CN;n is 0, 1 or 2;each R2is independently halo or OH;m is 1 or 2;R10is H or Ci-4alkyl;R11and R12are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; or R11and R12together with the carbon atom to which they are attached, form a C3-6cycloalkyl or 3-7 membered heterocycloalkyl which isA is -C=C-, phenyl or 5-6 membered monocyclic heteroaryl; wherein said phenyl or 5-6 membered monocyclic heteroaryl may each be independently substituted by one or two R20;each R20is independently CN, halo, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or C1-4haloalkoxy; andor a pharmaceutically acceptable salt thereof.

21. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is: (5S)- / V-{3-[4-(6-cyanopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(6-aminopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(5-aminopyrazin-2-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{4-[2-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(6-amino-5-methylpyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-fluoropyridin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-amino-4-methylpyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyridin-8-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[3-(4'-carbamoyl-3'-fluoro[1,1'-biphenyl]-4-yl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-(lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole- 2-carboxamide;(5S)-N-{3-[4-(2-aminopyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-[3-(4'-sulfamoyl[1,1'-biphenyl]-4-yl)oxetan-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-oxo-2,3-dihydro-1H-indol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(3-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-methoxypyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(cyanomethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[(3R)-3-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-(pyrimidin-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-(pyridin-3-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[6-(difluoromethyl)pyridin-3-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(5-methylpyridazin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[(3S)-3-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-methoxypyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(l-acetylpiperidin-4-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(6-fluoropyridin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(oxetan-3-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-methyl-l,3-thiazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(l-acetylpiperidin-4-yl)-5-methyl-lH-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-(l,3-thiazol-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(2-cyanoethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(5-fluoro-l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[l-(l,l-dioxo-lX6-thietan-3-yl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(3-cyanopyrazolo[l,5-a]pyrimidin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-(lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(l-methyl-lH-imidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(lH-benzotriazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(1,3-dimethyl-1H-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(l,2-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(3-methoxy-l-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-amino-4-methoxypyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-amino-lH-benzimidazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(5-amino-lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-aminopyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(6-aminopyridazin-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-amino[l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(l,4-dimethyl-lH-pyrazol-3-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl-N-{3-[4-([l,2,4]triazolo[l,5-a]pyrimidin-5-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(l-methyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(lH-imidazo[4,5-b]pyridin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(5-cyano-l-methyl-lH-pyrazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(6-amino-5-methylpyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-amino-4-ethylpyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2,4-diaminopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[2-amino-4-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(5-methyl-l,3-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{4-[2-(ethylamino)-4-(methylamino)pyrimidin-5-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-amino-5-methyl-l,3-oxazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(3H-imidazo[4,5-b]pyridin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(4-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-phenyl- / V-{3-[4-(l,3,4-thiadiazol-2-yl)phenyl]oxetan-3-yl}-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(6-aminopyrimidin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(2-amino-4-cyanopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{4-[(3RS)-3-carbamoylpiperidin-l-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(3-oxopiperazin-l-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(morpholin-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{4-[5-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(5-methyl-2H-1,2,3-triazol-4-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(4-amino-l-methyl-lH-pyrazol-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[3-(4-{1-[1-(2-methoxyethyl)piperidin-4-yl]-1H-pyrazol-4-yl}phenyl)oxetan-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)- / V-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[6-(2-aminopyrimidin-5-yl)pyridazin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(6-amino-4-methylpyridin-3-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-amino-4-methoxypyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(6-amino-4-methoxypyridin-3-yl)pyridazin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(2-amino-4-methylpyrimidin-5-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(3-methyl-1H-pyrazol-4-yl)pyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-amino-4-methylpyrimidin-5-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(2-aminopyrimidin-5-yl)pyrazin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-[l-(2'-amino[5,5'-bipyrimidin]-2-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[l-(2'-amino-4'-methyl[5,5'-bipyrimidin]-2-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[l-(2'-amino[2,5'-bipyrimidin]-5-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{1-[4-(2-aminopyrimidin-5-yl)-3-methylphenyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[4-(2-aminopyrimidin-5-yl)-2-methylphenyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-4-methylpyridin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyrazin-2-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[l-(6'-amino-3-methyl[2,3'-bipyridin]-5-yl)cyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-methyl-6-[l-(l-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{6-[l-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(1-{6-[2-(difluoromethyl)-2H-1,2,3-triazol-4-yl]-5-methylpyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-chloropyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-ethylpyridin-3-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)- / V-(l-{5-methyl-6-[l-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{5-methyl-6-[l-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[6-(l,5-dimethyl-1H-pyrazol-4-yl)-5-methylpyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[5-methyl-6-(lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-{3-[5-methyl-6-(5-methyl-lH-pyrazol-4-yl)pyridin-3-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{6-[l-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{6-[l-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{5-methyl-6-[1-(2H3)methyl-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-({6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}methyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}(2H2)methyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-[(lR)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[(lS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(2-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}propan-2-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[(lR,2S)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[(lS,2R)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methylcyclopropyl]-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-3-methoxycyclobutyl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(2-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-(3-cyanophenyl)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5R)-N-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5R)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5R)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylphenyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]pyridin-3-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methyl-l-oxo-lX5-pyridin-3-yl}oxetan-3-yl)-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{1-[1-(2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazol-4-yl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(3-{1-[2-(difluoromethyl)-2H-indazol-5-yl]-1H-pyrazol-4-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)- / V-{3-[l-(2-amino[l,2,4]triazolo[l,5-a]pyridin-7-yl)-1H-pyrazol-4-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{1-[2-(difluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]-1H-pyrazol-4-yl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(1-{1-[4-(difluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)- / V-(l-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-(3-{[l-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}oxetan-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{1-[(2-aminopyrimidin-5-yl)ethynyl]cyclopropyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-5-(3-cyanophenyl)-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-5-(3-cyanophenyl)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(3-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}oxetan-3-yl)-5-(3-fluorophenyl)- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-[(lR)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-[(lS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyridin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-[(lR)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)- / V-[(lS)-l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methylpyrazin-2-yl}ethyl]-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclobutyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclohexyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(4-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}oxan-4-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{(lS)-l-[4-(2-aminopyrimidin-5-yl)phenyl]propyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{(3R)-3-[4-(2-aminopyrimidin-5-yl)phenyl]oxolan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{(3S)-3-[4-(2-aminopyrimidin-5-yl)phenyl]oxolan-3-yl}-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[(lR)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methoxyethyl]-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-[(lS)-l-{6-[l-(difluoromethyl)-1H-pyrazol-4-yl]-5-methylpyridin-3-yl}-2-methoxyethyl]-5-phenyl- 6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{1-[4-(2-aminopyrimidin-5-yl)phenyl]-3,3-difluorocyclobutyl}-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S,7S)- / V-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S,7S)-N-{1-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S,7S)-N-{3-[5-(2-aminopyrimidin-5-yl)-6-methylpyridin-2-yl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S,7S)-N-{1-[6-(2-amino-4-methylpyrimidin-5-yl)pyridazin-3-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S,7S)-N-{1-[6-(2-aminopyrimidin-5-yl)-5-methylpyridin-3-yl]cyclopropyl}-7-fluoro-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S,7R)-N-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-{3-[4-(2-aminopyrimidin-5-yl)phenyl]oxetan-3-yl}-7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{3-chloro-4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-6-methoxypyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-methoxyphenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3,5-difluorophenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{5-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluoropyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{3-cyano-4-[l-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(l-{4-[l-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide;(5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethoxy)phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(1-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-methylpyridin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3,5-dimethylphenyl}cyclopropyl)-5-phenyl-6,7-dihydro- 5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5R)-N-(1-{3-(difluoromethoxy)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(1-{3-(difluoromethoxy)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(1-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyridin-3-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;(5S)-N-(1-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluoro-3-methoxyphenyl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; or(5S)-N-(1-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxypyrimidin-2-yl}cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide,or a pharmaceutically acceptable salt of any one thereof.

22. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, and at least one pharmaceutically acceptable excipient.

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, or the pharmaceutical composition according to claim 22, for use as a medicament.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, or the pharmaceutical composition according to claim 22, for use in the treatment of a disease in which inhibition of RIPK1 provides a prophylactic or therapeutic effect.

25. The compound for use, pharmaceutically acceptable salt for use or pharmaceutical composition for use according to claim 24, wherein the disease is an inflammatory disease, such as Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune lymphoproliferative syndrome (APS), arthritis (such as osteoarthritis), rheumatoid arthritis (RA), non-communicable inflammatory skin diseases (ncISD) (such as psoriasis (PsO) or atopic dermatitis (AD)), asthma, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), systemic sclerosis (SSc), chronic obstructive pulmonary disease (COPD), lysosomal storage disorders, sepsis, acute kidney disease (AKD), chronic kidney disease (CKD), Sjogren's syndrome (SjS), celiac disease, atherosclerosis, Crohn's disease (CD), colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematous (SLE), lupus or other forms of nephritis, Parkinson's disease or ulcerative colitis (UC).

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