Ripk1 inhibitors and methods of use thereof

Abstract

Described herein are compounds of Formula (I) I, or a pharmaceutically acceptable salt thereof. The compounds of Formula I act as RIPK1 inhibitors and can be used to prevent, treat, or act as a rescue agent for a RIPK1 -associated disease.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 595,482, filed November 2, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] field This article discloses novel RIPK1 inhibitors. These RIPK1 inhibitors can be used for the prevention, treatment, or as therapeutic agents for RIPK1-related diseases.

[0003] background Receptor-interacting protein-1 kinase (RIPK1) belongs to the serine / threonine protein kinase family involved in innate immune signaling. RIPK1 has emerged as a promising therapeutic target for treating a variety of human neurodegenerative diseases, autoimmune diseases, and inflammatory diseases. Extensive research supports this view, demonstrating that RIPK1 is a key mediator of apoptotic and necrotic cell death, as well as inflammatory pathways. For example, RIPK1 inhibition has been found to be a treatment for acute kidney injury (AKI), a devastating clinical condition caused by a variety of damages including ischemia-reperfusion, nephrotoxic drugs, and sepsis. RIPK1-mediated necroptosis has been found to play a significant role in AKI, and RIPK1 inhibitors may serve as promising clinical candidates for AKI treatment. Wang JN, Liu MM, Wang F, Wei B, Yang Q, Cai YT, Chen X, Liu XQ, Jiang L, Li C, Hu XW, Yu JT, Ma TT, Jin J, Wu YG, Li J, Meng XM, RIPK1 InhibitorCpd-71 Attenuates Renal Dysfunction in Cisplatin-Treated Mice via Attenuating Necroptosis, Inflammation and Oxidative Stress. Clin Sci (Lond). 2019 July 25;133(14):1609-1627.

[0004] Furthermore, human genetic evidence has linked abnormal regulation of RIPK1 to the pathogenesis of amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis, and other inflammatory and neurodegenerative diseases. (Alexei Degterev, Dimitry Ofengeim, and Junying Yuan)Targeting RIPK1 for the treatment of human diseases , PNAS, May 14, 2019, 116 (20), 9714-9722; Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y et al., RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS , Science, 2016,353:603–8; Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS et al., Necroptosis activation in Alzheimer's disease , Nat Neurosci, 2017, 20:1236–46; Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP et al., Activation of necroptosis in multiple sclerosis, Cell Rep., 2015, 10:1836–49.

[0005] It has also been confirmed that necroptosis is a delayed component of ischemic neuronal injury; therefore, RIPK1 inhibition may play a promising role as a stroke treatment. (Degterev A et al.,) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury ,Nat Chem Biol 2005, 1(2):112-119.

[0006] Therefore, there is a need for highly selective RIPK1 inhibitors that can cross the blood-brain barrier, thereby providing the possibility of targeting neuroinflammation and cell death, which drive various neurological conditions, including Alzheimer's disease, ALS, and multiple sclerosis, as well as acute neurological diseases such as stroke and traumatic brain injury. Invention Overview This article describes compounds of formula I: Or a pharmaceutically acceptable salt thereof, wherein A, R 1 R 2 And n is described below.

[0008] The compounds described in this article are RIPK1 inhibitors, which can be used to prevent, treat or improve neurodegenerative diseases, autoimmune diseases, inflammatory diseases and other RIPK1-related diseases.

[0009] This article also describes methods for treating neurodegenerative diseases, autoimmune diseases, and inflammatory diseases, which include administering the compounds described herein or pharmaceutically acceptable salts thereof to patients in need.

[0010] This article also describes the use of the compounds described herein or pharmaceutically acceptable salts thereof for the treatment of neurodegenerative diseases, autoimmune diseases, and inflammatory diseases in patients in need of such treatment.

[0011] This article also describes pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0012] This article also describes pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers.

[0013] This article also describes methods for treating neurodegenerative diseases, autoimmune diseases, and inflammatory diseases, which include administering the compounds described herein or pharmaceutically acceptable salts thereof, along with at least one additional therapeutic agent, to patients in need.

[0014] This article also describes the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in combination with at least one other pharmaceutical agent, for the treatment of degenerative diseases, autoimmune diseases, and inflammatory diseases in patients in need of such treatment.

[0015] This article also describes pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0016] This article also describes pharmaceutical compositions comprising the compounds described herein, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0017] The overview of the technology described above is non-limiting, and other features and advantages of the technology will become apparent from the following detailed description and claims. Invention Details This article describes compounds of formula I: Or its pharmaceutically acceptable salt, wherein: for or ; R 1 For –(R 7 )mR 8 ; R 2 It is H or (C1-C6) alkyl; R 3 It is H or halogen; R4 It is H or halogen; R 5 It is H or halogen; R 6 It is H or halogen; R 7 It is (C1-C6)alkyl or (C1-C6)carbonyl; R 8 for a) An aryl group, optionally substituted with up to three of the following groups: halogen, O(C1-C6)alkyl, O(C3-C6)cycloalkyl, (C3-C8)cycloalkyl optionally substituted with a nitrile group, O-(C1-C6)alkyl-O-CH3, C(O)NH2, (C1-C6)alkyl optionally substituted with up to three halogens, S(O)2-CH3, (C1-C6)nitrile, ((C1-C6)alkyl) having up to three heteroatoms selected from N, O and S and further optionally substituted with (C1-C6)alkyl. p -(C5-C6)heteroaryl, wherein the (C1-C6)alkyl group is optionally substituted with up to 3 halogens; b) A heteroaryl group having up to five heteroatoms selected from N, O, and S, and optionally substituted by up to three of the following groups: halogen, O(C1-C6)alkyl, O(C1-C6)alkyl-F, S(C1-C6)alkyl, C(O)NH2, (C1-C6)alkyl optionally substituted by up to three halogens, (C1-C6)nitrile, (C3-C8)cycloalkyl optionally substituted by a nitrile group, ((C1-C6)alkyl) p -Aryl, having up to 3 heteroatoms selected from N, O and S ((C1-C6)alkyl) p -(C5-C6) heterocyclic group, having up to 3 heteroatoms selected from N, O and S, optionally substituted with (C1-C6)alkyl groups ((C1-C6)alkyl). p -(C5-C6)heteroaryl, optionally substituted with (C5-C6)heterocyclic ((C1-C6)alkyl) p -(C5-C6)cycloalkyl, wherein the (C5-C6) heterocyclic group has up to 3 heteroatoms selected from N, O, and S and is further optionally substituted with (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with up to 3 halogens; O-(C5-C6) heterocyclic group having up to 3 heteroatoms selected from N, O, and S; (C5-C6) heteroaryl group having up to 3 heteroatoms selected from N, O, and S and further optionally substituted with (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with up to 3 halogens; or c) Cycloalkyl; B is either CH or N; D is either C or N, provided that if D is N, then R 3 It does not exist; E is either C or N, provided that if E is N, then R 6 It does not exist; G is either CH or N; J is either CH or N; m is 0 or 1; n is 0 or 1; and p is 0 or 1.

[0019] In some embodiments of the present invention, A is... .

[0020] In some embodiments of the present invention, B is CH and D and E are C.

[0021] In a specific embodiment of the present invention, both D and E are N.

[0022] In a further embodiment of the invention, E is N.

[0023] In a further embodiment of the invention, R 4 and R 6 All are F.

[0024] In some embodiments of the present invention, R 5 It is F.

[0025] In other embodiments of the invention, R 2 For H.

[0026] In other specific embodiments of the invention, R 7 It is an (C1-C6) alkyl group and m is 1.

[0027] In a further embodiment of the present invention, m is 0.

[0028] In some embodiments of the present invention, R 8 It is aryl. In a specific embodiment of the invention, R 8 The aryl group is substituted with up to three halogens. In another embodiment of the invention, R 8 The aryl group is substituted with an O (C1-C6) alkyl group. In some embodiments of the invention, R 8 The aryl group is substituted with a (C3-C8) cycloalkyl group, wherein the (C3-C8) cycloalkyl group is optionally substituted with a nitrile group. In a further embodiment of the invention, R 8 The aryl group is substituted with an O (C3-C6) cycloalkyl group. In a further embodiment of the invention, R 8 It is an aryl group substituted with O-(C1-C6)alkyl-O-CH3. In another embodiment of the invention, R8 The aryl group is replaced by C(O)NH2. In a further embodiment of the invention, R 8 The aryl group is substituted with a (C1-C6) alkyl group, wherein the (C1-C6) alkyl group is optionally substituted with up to three halogens. In a further embodiment of the invention, R 8 The aryl group is replaced by S(O)2-CH3. In another embodiment of the invention, R 8 The aryl group is replaced by a (C1-C6) nitrile group. In a specific embodiment of the invention, R 8 It is a (C1-C6)alkyl group having at most 3 heteroatoms selected from N, O and S. p -(C5-C6) heteroaryl-substituted aryl groups. In a further specific embodiment of the invention, R 8 For ((C1-C6)alkyl) p -(C5-C6)heteroaryl-substituted aryl groups, wherein the ((C1-C6)alkyl) p -(C5-C6)heteroaryl groups have up to three heteroatoms selected from N, O, and S, further bonded by (C1-C6) heteroatoms. 6) Alkyl substitution. In another embodiment of the invention, R 8 For ((C1-C6)alkyl) p -(C5-C6)heteroaryl-substituted aryl groups, wherein the ((C1-C6)alkyl) p -(C5-C6)heteroaryl has up to 3 heteroatoms selected from N, O and S, and is further substituted with (C1-C6)alkyl, which is further substituted with up to 3 halogens.

[0029] In some embodiments of the present invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S. In other specific embodiments of the invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, and wherein said heteroaryl group is substituted with up to three halogens. In another embodiment of the invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with an O (C1-C6) alkyl group. In some embodiments of the invention, R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, and wherein said heteroaryl group is surrounded by ((C1-C6)alkyl). p -Aryl substitution. In some embodiments of the invention, R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O, and S, and wherein said heteroaryl group is surrounded by a ((C1-C6)alkyl group having up to 3 heteroatoms selected from N, O, and S.p -(C5-C6) heterocyclic substitution. In a further embodiment of the invention, R... 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with O (C1-C6) alkyl-F. In a further embodiment of the invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with an S (C1-C6) alkyl group. In another embodiment of the invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with C(O)NH2. In a further embodiment of the invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with a (C1-C6) alkyl group. In a further embodiment of the invention, R 8 The heteroaryl group is a heteroatom having up to five heteroatoms selected from N, O, and S, wherein the heteroaryl group is substituted with a (C1-C6) alkyl group, and the (C1-C6) alkyl group is further substituted with up to three halogens. In another embodiment of the invention, R 8 It is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with a (C1-C6) nitrile group. In a further embodiment of the invention, R 8 It is a heteroaryl group having at most five heteroatoms selected from N, O, and S, wherein said heteroaryl group is substituted with a (C3-C8) cycloalkyl group. In a further embodiment of the invention, R 8 The heteroaryl group is a heteroatom having at most five heteroatoms selected from N, O, and S, wherein the heteroaryl group is substituted with a (C3-C8) cycloalkyl group, and the (C3-C8) cycloalkyl group is further substituted with a nitrile group. In another embodiment of the invention, R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O, and S, and wherein said heteroaryl group is surrounded by a ((C1-C6)alkyl group having up to 3 heteroatoms selected from N, O, and S. p -(C5-C6) heteroaryl substitution. In some embodiments of the invention, R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O, and S, and wherein said heteroaryl group is surrounded by a ((C1-C6)alkyl group having up to 3 heteroatoms selected from N, O, and S. p -(C5-C6) heteroaryl substitution, wherein the ((C1-C6) alkyl) p -(C5-C6) heteroaryl groups are further substituted with (C1-C6) alkyl groups. In a further embodiment of the invention, R 8It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, and wherein said heteroaryl group is surrounded by ((C1-C6)alkyl). p -(C5-C6)cycloalkyl substitution. In a further embodiment of the invention, R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, and wherein said heteroaryl group is surrounded by ((C1-C6)alkyl). p -(C5-C6)cycloalkyl substitution, wherein the ((C1-C6)alkyl) p -(C5-C6)cycloalkyl groups are substituted with (C5-C6) heterocyclic groups having up to three heteroatoms selected from N, O, and S. In a particular embodiment of the invention, R 8 A heteroaryl group having up to 5 heteroatoms selected from N, O, and S, wherein the heteroaryl group is surrounded by ((C1-C6)alkyl). p -(C5-C6)cycloalkyl substitution, wherein the ((C1-C6)alkyl) p The (C5-C6)cycloalkyl group is substituted with a (C5-C6) heterocyclic group having up to three heteroatoms selected from N, O, and S, wherein the (C5-C6) heterocyclic group is substituted with a (C1-C6) alkyl group. In a more specific embodiment of the invention, R 8 A heteroaryl group having up to 5 heteroatoms selected from N, O, and S, wherein the heteroaryl group is surrounded by ((C1-C6)alkyl). p -(C5-C6)cycloalkyl substitution, wherein the ((C1-C6)alkyl) p The (C5-C6)cycloalkyl group is substituted with a (C5-C6) heterocyclic group having up to three heteroatoms selected from N, O, and S, wherein the (C5-C6) heterocyclic group is substituted with a (C1-C6) alkyl group, and the (C1-C6) alkyl group is substituted with up to three halogens. In another embodiment of the invention, R 8 The heteroaryl group is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein the heteroaryl group is substituted with an O-(C5-C6) heterocyclic group having up to three heteroatoms selected from N, O, and S. In some embodiments of the invention, R 8 The heteroaryl group is a heteroaryl group having up to five heteroatoms selected from N, O, and S, and wherein said heteroaryl group is substituted with a (C5-C6) heteroaryl group having up to three heteroatoms selected from N, O, and S. In other embodiments of the invention, R 8 The heteroaryl group is a heteroaryl group having up to five heteroatoms selected from N, O, and S, wherein the heteroaryl group is substituted with a (C5-C6) heteroaryl group having up to three heteroatoms selected from N, O, and S, and the (C5-C6) heteroaryl group is further substituted with a (C1-C6) alkyl group. In another embodiment of the invention, R 8It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, wherein the heteroaryl group is substituted with a (C5-C6) heteroaryl group having up to 3 heteroatoms selected from N, O and S, the (C5-C6) heteroaryl group is further substituted with a (C1-C6) alkyl group, and the (C1-C6) alkyl group is further substituted with up to 3 halogens.

[0030] In some embodiments of the present invention, R 8 It is a cycloalkyl group.

[0031] In a particular embodiment of the present invention, n is 0.

[0032] In other specific embodiments of the invention, n is 1.

[0033] In a particular embodiment of the invention, p is 0.

[0034] In other specific embodiments of the invention, p is 1.

[0035] In a specific embodiment of the present invention, the compound of formula I is selected from: ((1r),4R,5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1s),4R,5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1r),4R,5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1s),4R,5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3R,5'S,7a'R)-3-(benzyloxy)-5'-(5-fluoropyridin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1r),3R,5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1s),3R,5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; cis-6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; trans-6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxamide; cis-6-((((1r),3R,5'(S),7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; trans-6-((((1s),3R,5'(S),7a'R)-5'-(1-methyl-1H-pyrazole-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; cis-6-((((1r),3R,5'(R),7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile; trans-6-((((1s),3R,5'(R),7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; (1r,3R,5'S,7a'R)-3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3S,5'S,7a'R)-3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-Fluoro-4-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)benzylnitrile; 5-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-2-carboxynitrile; 4-Fluoro-3-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-5'-phenyl-3-{[2-(trifluoromethyl)pyridin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-[(5-methoxypyridin-3-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(3-fluoropyridin-4-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-{[5-(trifluoromethyl)pyridin-3-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-(3-fluorophenoxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(2-chloropyridin-4-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,2-benzothiazol-4-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(4-fluoro-3-methylphenoxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,2-benzothiazol-5-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-[3-(trifluoromethyl)phenoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[3-(1,3,4-oxadiazol-2-yl)phenoxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(4-fluoro-3-methoxyphenoxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,2-benzoxazol-7-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(imidazo[1,2-c]pyrimidin-5-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-[(pyrrolo[1,2-b]pyridazin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-(pyrrolo[1,2-b]pyridazine-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-[(pyrrolo[1,2-d][1,2,4]triazine-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 6-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; (5'S,7a'R)-3-((6-chloropyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-{[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(2-methyl[1,3]thiazo[5,4-d]pyrimidin-7-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-{[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-fluoropyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-{[6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 6-(((1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; (1s,3S,5'S,7a'R)-3-((6-chloropyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-2-carboxynitrile; 5-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-3-carboxynitrile; 6-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrazine-2-carboxynitrile; 6-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; 4-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-2-carboxynitrile; 2-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; 2-{[(1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-4-carboxynitrile; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(2-methylpyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(thieno[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(furano[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(6-methylfurano[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(6-methylthiopheno[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-[(imidazo[1,2-c]pyrimidin-5-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((5-fluoropyridin-2-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-[(2-chloropyridin-3-yl)oxy]-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(5-fluoropyridin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; cis-(5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(3-fluoropyridin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; trans-(5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(3-fluoropyridin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; cis-6-{[(5'S,7a'R)-5'-(2,3-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; trans-6-{[(5'S,7a'R)-5'-(2,3-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-4-carboxynitrile; 6-(((5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile; 6-{[(5'S,7a'R)-5'-(2-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-4-carboxynitrile; 6-(((5'S,7a'R)-5'-(3-cyano-5-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; (1s,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 6-{[(5'S,7a'R)-5'-(5-fluoropyridin-2-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-[(5-fluoropyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-{[(1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-3-carboxynitrile; 6-(((5'R,7a'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile; (1s,3R,5'R,7a'S)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-4-[(pyrazin-2-yl)oxy]tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-((6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-((6-(4-(difluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile; 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide; (1r,3R,5'S,7a'R)-3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile; 2-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide; 2-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide; (1r,3R,5'S,7a'R)-3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-3-((7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 4-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazine-7-carboxynitrile; 4-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazine-7-carboxynitrile; cis-(1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-(5-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; trans-(1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-(5-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-(3-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1S,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-(3-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1R,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((s)-1-(3-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylpyridinecarboxylate; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylbenzoate; ((1S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-phenoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-phenoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1R),(5'S,7a'R)-5'-(5-fluoropyridin-3-yl)-4-phenoxytetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1S),(5'S,7a'R)-5'-(5-fluoropyridin-3-yl)-4-phenoxytetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-((((1S),3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisocyanonitrile; 2-((((1R),3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisocyanonitrile; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[(imidazo[1,2-a]pyrazin-8-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[([1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[(pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[(pyridin-4-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3-fluoropyridin-2-yl)-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyrazin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1S,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-ylmethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[([1,2,4]triazolo[4,3-a]pyrimidin-6-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1-cyclopropyl-1H-pyrazole-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(pyrazolo[1,5-a]pyrimidin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1-methyl-1H-pyrazole-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1-phenyl-1H-pyrazole-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-ethoxypyrimidin-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-({3-[2-(4H-1,2,4-triazol-4-yl)ethyl]phenyl}methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[5-(difluoromethyl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-benzyl-1,3,4-thiadiazol-2-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({6-[(but-2-yl)oxy]pyridin-2-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)quinoline-8-carboxynitrile; (5'S)-3-{[5-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[3-(methylthio)[1,2,4]triazolo[4,3-a]pyridin-6-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[4-(methanesulfonyl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-b]pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-d]pyrimidin-6-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(4-fluoroisoquinoline-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1s,3S,5'S,7a'R)-3-[(1,3-benzothiazo-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[2-(morpholin-4-yl)pyrimidin-5-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({4-[(1H-imidazol-1-yl)methyl]phenyl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-({3-[(1H-1,2,3-triazol-1-yl)methyl]phenyl}methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-(2-fluoroethoxy)pyridin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 1-[5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]cyclobutane-1-carboxynitrile; 1-[3-chloro-4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]cyclopropane-1-carboxynitrile; (5'S)-3-{[4-(1,2-oxazol-3-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(pyrazolo[1,5-a]pyrimidin-7-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-methoxy-1,7-naphthyl-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-chloro-2-(1,3-oxazol-5-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-methoxyimidazo[1,2-a]pyridin-7-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[6-(morpholin-4-yl)pyridin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(isoquinolin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [2-Methoxy-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[4-(1H-imidazol-1-yl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-(cyclobutoxy)-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-3-[(2-methoxy-8-methylquinoline-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(5,6,7,8-tetrahydroquinolin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[3,2-b]pyridin-2-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[6-(2-fluoroethoxy)pyridazin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridine-4-carboxylonitrile; (5'S)-3-[(imidazo[1,2-a]pyrimidin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-[4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]propionitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)-1,3-benzothiazo-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-chloro-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]acetonitrile; (5'S)-3-{[4-(2-methoxyethoxy)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-Fluoro-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[1-(pyridin-4-yl)-1H-pyrazol-4-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(1H-pyrazol-1-yl)phenyl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)furan-3-carboxynitrile; (5'S)-3-{[4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({6-[(oxan-4-yl)oxy]pyridin-3-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[4-(1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1,2-benzoxazol-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(pyrazolo[1,5-a]pyrimidin-7-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1,3-benzothiazo-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[5-(difluoromethyl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-benzyl-1,3,4-thiadiazol-2-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)quinoline-8-carboxynitrile; (5'S,7a'R)-3-({6-[(but-2-yl)oxy]pyridin-2-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[4-(methanesulfonyl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-b]pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(6-methoxypyridin-3-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-cyclopropyl-1,3-thiazolyl-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(4-fluoroisoquinoline-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({4-[(1H-imidazol-1-yl)methyl]phenyl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-Methoxy-6-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridine-2-carboxynitrile; (5'S)-5'-(pyrazin-2-yl)-3-({3-[(1H-1,2,3-triazol-1-yl)methyl]phenyl}methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-(2-fluoroethoxy)pyridin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 1-[5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]cyclobutane-1-carboxynitrile; 1-[3-chloro-4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]cyclopropane-1-carboxynitrile; (5'S)-3-{[4-(1,2-oxazol-3-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-methoxy-1,7-naphthyl-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-chloro-2-(1,3-oxazol-5-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-methoxyimidazo[1,2-a]pyridin-7-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(isoquinolin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [2-Methoxy-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[4-(1H-imidazol-1-yl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-(cyclobutoxy)-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-3-[(2-methoxy-8-methylquinoline-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(5,6,7,8-tetrahydroquinolin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[3,2-b]pyridin-2-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2,3-dihydro-1-benzofuran-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridine-4-carboxylonitrile; (5'S)-3-[(imidazo[1,2-a]pyrimidin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-[4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]propionitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)-1,3-benzothiazo-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-chloro-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]acetonitrile; (5'S)-3-{[4-(2-methoxyethoxy)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-Fluoro-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[1-(pyridin-4-yl)-1H-pyrazol-4-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(1H-pyrazol-1-yl)phenyl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)furan-3-carboxynitrile; (5'S)-3-{[4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({6-[(oxan-4-yl)oxy]pyridin-3-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-(thieno[2,3-d]pyrimidin-6-ylmethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S)-3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-(3-(1-methyl-1H-pyrazol-5-yl)phenoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; 3-Fluoro-5-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-(3,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-{[(1s,3S,5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(6-methylpyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-(1-methyl-1H-pyrazol-3-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-[3-(1-methyl-1H-pyrazol-5-yl)phenoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(6-methylpyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-(3-(1-methyl-1H-pyrazol-5-yl)phenoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(pyridin-2-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(2-methyl-2H-indazol-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[([1,2,4]triazolo[4,3-a]pyrimidin-5-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(2-methylpyridin-3-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,3-benzothiazo-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 1-[4-({[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]cyclopropane-1-carboxynitrile; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-(1-methyl-1H-pyrazol-3-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; cis-(1s,3S,5'S,7'S,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; trans-(1s,3S,5'S,7'R,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 5'-(5-Fluoropyridin-2-yl)-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(pyrazin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(2,5-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-((((5' S ,7a' R )-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazolyl]-3-yl)oxy)methyl)benzylnitrile; (5' S ,7a' R )-3-(benzo[ d Isoxazol-6-ylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; cis-(5'S,7a'R)-3-[3-(1-methyl-1H-pyrazol-5-yl)phenoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; trans-(5'S,7a'R)-3-[3-(1-methyl-1H-pyrazole-5-yl)phenoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-phenoxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-b]pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[6-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl]oxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(pyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(3,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1S,3S,5'S,7a'R)-3-((2-chlorobenzyl)oxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-Fluoro-5-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; 4-((((5' S ,7a' R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazolyl]-3-yl)oxy)methyl)benzylnitrile; (5' S ,7a' R )-3-((5-chloro-3-methylpyridin-2-yl)methoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazol]-3'-one; (5' S ,7a' R )-5'-(pyrazin-2-yl)-3-(thiophen-2-ylmethoxy)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-[(3-fluorophenyl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(3-chlorophenyl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-({[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S,7a'R)-3-[(3-fluorophenyl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(cyclobutylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; cis-(5'S,7a'R)-3-(cyclopentylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H-spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazol]-3'-one; and trans-(5'S,7a'R)-3-(cyclopentylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0036] In a more specific embodiment of the invention, the compound of formula I is selected from: .

[0037] definition The following lists the definitions of various terms used herein. Unless otherwise limited in the specific circumstances, these definitions apply to terms used throughout this specification and claims, whether used alone or as part of a larger group.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature and laboratory procedures used herein in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly used in the art.

[0039] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical objects of that article. For example, “an element” means one element or more. Furthermore, the use of the term “including” and other forms such as “contains” is non-restrictive.

[0040] As used in this article, in quantitative terms the term “about” means 10% or less of the value it modifies (rounded to the nearest integer if the value cannot be subdivided, such as several molecules or nucleotides).

[0041] All ranges disclosed herein include the listed endpoints and can be combined independently (e.g., the range “50 mg to 500 mg” includes the endpoints 50 mg and 500 mg, as well as all intermediate values). The endpoints and any values ​​of the ranges disclosed herein are not limited to precise ranges or values; they have sufficient imprecision to include values ​​that approximate these ranges and / or values.

[0042] As used herein, the term "comprising" may include embodiments of "consisting of" and "substantially consisting of". As used herein, the terms "comprising", "including", "having", "may", "containing", and variations thereof are intended as open-ended transitional phrases, terms, or words that require the presence of a specified ingredient / step and allow for the presence of other ingredients / steps. However, such descriptions should be construed as also describing the composition or method as "consisting of the listed components" and "substantially consisting of the listed components", which allows for the presence of only the specified component or compound, along with any acceptable carrier or fluid, and excludes other components or compounds.

[0043] The term "halogen" includes fluorine, chlorine, bromine, or iodine.

[0044] The term "C1-C6 alkyl" encompasses straight-chain alkyl groups having 1 to 6 carbon atoms and branched alkyl groups having 3 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-1-methylpropyl, etc.

[0045] The term "C3-C6 cycloalkyl" encompasses bridging, saturated, or unsaturated cycloalkyl groups having 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C3-C" 10 "Cycloalkyl" encompasses bridged, saturated, or unsaturated cycloalkyl groups having 3 to 10 carbon atoms. "Cycloalkyl" also includes non-aromatic rings and monocyclic non-aromatic rings fused to saturated cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, etc. Examples described by structure include... .

[0046] The term "heteroaryl" refers to a monocyclic or polycyclic (including bicyclic) aromatic heterocyclic alkyl group containing at least one cyclic heteroatom selected from O, S, and N. Examples of heteroaryl groups include pyridinyl, oxazolyl, azirzothiazole, benzothiazole, imidazolyl, triazolyl, furanyl, triazinyl, thiopheneyl, pyrimidinyl, pyrazinyl, indazinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxalinyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, etc.

[0047] The term "heterocyclic alkyl" refers to a monocyclic or bicyclic or bridged, partially unsaturated or saturated ring containing at least one heteroatom selected from N, S, and O, each ring having 3 to 10 atoms, wherein the connecting point can be carbon or nitrogen. Examples include nitrogen-containing heterocyclic butanes, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazineyl, dioxyl, imidazoalkyl, 2,3-dihydrofuran (2,3- b )pyridyl, benzoxazinyl, benzoxazolinyl, 2- H -phthalazinyl, isoindolinyl, benzoxazinyl, 5,6-dihydroimidazo[2,1- b Thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, etc. The term also includes partially unsaturated non-aromatic monocyclic compounds, such as 2- or 4-pyridones linked by nitrogen. n -replaced-(1) H ,3 H )-Pyrimidine-2,4-dione ( N -Substituted uracil). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl and azabicyclo[2.2.1]heptyl. Examples described by structure include .

[0048] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including inorganic or organic bases and inorganic or organic acids). The term "pharmaceutically acceptable salt" includes salts of basic compounds that are non-toxic salts of the compounds of this invention, which are typically prepared by reacting a free base with a suitable organic or inorganic acid. Salts of the representative basic compounds of the present invention include, but are not limited to, the following: acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, camphorsulfonates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, ethanedisulfonates, etopoates, ethanesulfonates, fumarates, gluconate, gluconate, glutamate, glycolyllarsanilate, hexylresorcinol salts, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, iodides, isothiosulfates, lactates, lactobionates, laurates, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalenesulfonates, and nitrates. N 1,3-methylglucosamine ammonium salts, oleates, oxalates, pyrazine (dihydroxynaphthyl salt), palmitates, pantothenates, phosphates / bisphosphonates, polygalacturonic acids, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, 8-chlorotheophylline salts, toluenesulfonates, triethyliodide, and valerates. Furthermore, in cases where the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric (Fe3+), ferrous (Fe2+), lithium, magnesium, ferric (Fe3+), ferrous (Fe2+), potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic alkalis include the following: primary amines, secondary and tertiary amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidinyl, glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0049] The term "patient" refers to a mammalian patient who is receiving or about to receive medical treatment, preferably a human patient.

[0050] The compounds of the present invention may contain one or more asymmetric centers, and therefore may exist as racemates, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The present invention is intended to include all such isomeric forms of these compounds.

[0051] Some of the compounds described herein contain alkene double bonds, and unless otherwise stated, are intended to include... E and Z Two geometric isomers.

[0052] Some of the compounds described herein contain substituted cycloalkanes having cis- and trans-isomers, and unless otherwise stated, are intended to include both cis- and trans-geometric isomers.

[0053] As is known in the art, the independent synthesis of these diastereomers or their chromatographic separation can be achieved by appropriately modifying the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline products or intermediates, which, if necessary, are derivatized with reagents containing asymmetric centers of known absolute configuration. If desired, racemic mixtures of compounds can be separated to isolate individual enantiomers. This separation can be carried out by methods well known in the art, such as coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomer mixture, followed by separation of individual diastereomers by standard methods (e.g., stepwise crystallization or chromatography). The coupling reaction often uses an enantiomerically pure acid or base to form a salt. The diastereomeric derivatives can then be converted to pure enantiomers by cleavage of the added chiral residues. Racemic mixtures of compounds can also be directly separated by chromatography using a chiral stationary phase, methods well known in the art.

[0054] Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure raw materials or reagents of known configurations, through methods well known in the art.

[0055] It should be understood that the present invention is intended to include pharmaceutically acceptable salts of the compounds described herein, and also to include non-pharmaceutically acceptable salts when they are used as precursors to the free compound or its pharmaceutically acceptable salts or in other synthetic operations.

[0056] Solvates of compounds with the structures described herein, and especially hydrates thereof, are also included in this invention.

[0057] Some of the compounds described herein can exist as tautomers with different hydrogen connection sites and accompanied by one or more double bond transfers. For example, ketones and their enol forms are keto-enol tautomers. The compounds of the present invention include individual tautomers as well as mixtures thereof.

[0058] In the compounds described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched to have the same atomic number but a different atomic mass or mass number than a specific isotope found predominantly in nature. The invention is intended to include all suitable isotopic variants of compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (… 1 H) and deuterium ( 2 (H). Protium is the dominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing the half-life in vivo or reducing dosage requirements, or it can provide compounds that can be used as standards for characterizing biological samples. 3 H, 11 C 18 F-labeled compounds can be used for PET, SPECT, or other imaging studies. Isotope-enriched compounds can be prepared using conventional techniques well-known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, using appropriate isotope-enriching reagents or intermediates, without excessive experimentation.

[0059] It should be noted that chemically unstable compounds are excluded from the embodiments included herein.

[0060] Treatment The compounds described herein can be used, in particular, for the prevention, treatment, or improvement of RIPK1-mediated diseases or disorders. Such RIPK1-mediated diseases or disorders may be regulated, at least in part, through programmed necrosis, apoptosis, or the production of inflammatory cytokines, especially inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), and Sjogren's syndrome. Symptoms, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / disease (non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen poisoning, liver poisoning), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage / injury (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), breast cancer Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplanted organs, tissues, and cells), ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, hypoxic-ischemic brain injury, ischemic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, Burns, multiple sclerosis, type 1 diabetes, type 2 diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's syndrome, interleukin-1 converting enzyme (ICE, also known as caspase-1)-aspartate proteolytic enzyme, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutation (mutation of the NF-κ-B essential regulatory gene (also known as IKKγ or IKKG)).In particular, NEMO deficiency syndrome, HOIL-1 deficiency (also known as RBCK1), heme oxidation IRP 2 ubiquitin ligase-1 deficiency, linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (e.g., influenza, Staphylococcus and Mycobacterium (tuberculosis)), and lysosomal storage diseases (especially Gaucher disease, and including GM2 ganglioside storage disease, α-mannoside storage disease, aspartate glucosamineuria, cholesterol ester storage disease, chronic hexosaminease A). Deficiencies, cystine storage disorders, Danon's disease, Fabry's disease, Farber's disease, fucoside storage disorders, galactosylsialic acid storage disorders, GM1 ganglioside storage disorders, mucolipid storage disorders, infantile free sialic acid storage disorders, adolescent hexosamine A deficiency, Krabbe's disease, lysosomal acid lipase deficiency, metachromatic leukoderma, mucopolysaccharide storage disorders, multiple sulfatase deficiencies, Niemann-Pick (N... Iemann-Pick disease, neuronal ceroid lipofuscin deposition disease, Pompe disease, osteogenesis imperfecta condensans, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs and Wolman diseases, Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastatic tumors, breast cancer, non-small cell lung cancer (NSCLC), radiation-induced necrosis, ischemic kidney injury, ocular ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / relief, hearing impairment (e.g., noise-induced hearing loss and ototoxicity-related drugs (e.g., cisplatin)), or for treating isolated cells to maintain viability and function.

[0061] The compounds of the formula described herein, or their pharmaceutically acceptable salts, may be used, in particular, to treat the following RIPK1-mediated diseases or disorders: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondylitis, gout, generalized juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, and osteoarthritis. Liver injury / disease (non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, liver poisoning), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney injury / damage (nephritis, kidney transplantation, surgery, use of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune IT) P), transplant rejection (rejection of transplanted organs, tissues, and cells), ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, hypoxic-ischemic brain injury of the newborn, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, Pulmonary sarcoidosis, Bechtel syndrome, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, melanoma, metastatic tumors, breast cancer, non-small cell lung cancer (NSCLC), radiation-induced necrosis, ischemic kidney injury, ocular ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, periodontitis, NEMO-mutation (mutation of an essential regulatory gene for NF-κ-B (also known as IKKγ or IKKG)).In particular, NEMO deficiency syndrome, HOIL-1 deficiency (also known as RBCK1 heme oxidation IRP 2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (e.g., influenza, Staphylococcus and Mycobacterium (tuberculosis)), and lysosomal storage diseases (especially Gaucher disease, and including GM2 ganglioside storage disease, α-mannoside storage disease, aspartate glucosamineuria, cholesterol ester storage disease, chronic hexosaminease A deficiency, cystine storage disease, Danon disease, Fabry disease, Fabry disease, fucoside storage disease, galactosylsialic acid storage disease, GM1 ganglioside storage disease). Diseases including mucolipid storage diseases, infantile free sialic acid storage diseases, adolescent hexosamine A deficiency, Krabby's disease, lysosomal acid lipase deficiency, metachromatic leukoencephalopathy, mucopolysaccharide storage diseases, multiple sulfatase deficiencies, Niemann-Pick disease, neuronal ceroid lipofuscin deposition disease, Pompe disease, osteogenesis imperfecta condensans, Sandhof's disease, Schindler's disease, sialic acid storage diseases, Tai-Sachs II disease and Wollman's disease, spinal cord injury, Sch-Jones syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and / or for processing isolated cells to maintain viability and function.

[0062] The compounds of the formula described herein, or their pharmaceutically acceptable salts, can be used to treat glaucoma.

[0063] The compounds of the formula described herein, or their pharmaceutically acceptable salts, may be used, in particular, to treat pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma.

[0064] The compounds of the formula described herein, or their pharmaceutically acceptable salts, may be used, in particular, to treat the following RIPK1-mediated diseases or disorders: rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), and psoriasis.

[0065] More specifically, the treatment of the diseases / disorders mentioned above may involve improving persistent organ damage or injury due to said disease / disorder. For example, the compounds of the present invention can be used in particular to improve brain tissue damage or injury following ischemic or traumatic brain injury, or to improve cardiac tissue damage or injury following myocardial infarction, or to improve brain tissue damage or injury associated with Huntington's disease, Alzheimer's disease, or Parkinson's disease, or to improve liver tissue damage or injury associated with non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, or primary sclerosing cholangitis, or acetaminophen overdose.

[0066] The compounds of the present invention can be used, in particular, to improve organ damage or impairment caused by radiation therapy, or to improve spinal cord injury or impairment following spinal cord injury, or to improve liver injury or impairment associated with acute liver failure. The compounds of the present invention can also be used, in particular, to improve hearing impairment, such as noise-induced hearing loss or hearing impairment following administration of ototoxic drugs or substances (e.g., cisplatin).

[0067] The compounds of the present invention can be used, in particular, to improve damage or injury to solid organ tissues (especially the kidneys, liver, and heart and / or lungs) following transplantation or administration of nephrotoxic drugs or substances (e.g., cisplatin). It should be understood that, where possible, such tissue damage can be improved by pretreatment with compounds of the formula described herein or pharmaceutically acceptable salts thereof; for example, by pretreatment of a patient before cisplatin administration or by pretreatment of an organ or organ recipient before transplantation. Improvement of such tissue damage can also be achieved by treatment during transplantation with compounds of the formula described herein or pharmaceutically acceptable salts thereof.

[0068] Such tissue damage can also be improved by short-term treatment of patients with compounds of the formula described herein or their pharmaceutically acceptable salts after transplantation surgery.

[0069] In one embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat retinal detachment, macular degeneration, and retinitis pigmentosa.

[0070] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat multiple sclerosis.

[0071] In one embodiment, a compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat traumatic brain injury.

[0072] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat Huntington's disease or Niemann-Pick disease.

[0073] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof may be used to treat amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer's disease.

[0074] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat age-related macular degeneration.

[0075] Treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Niemann-Pick disease may more specifically involve improving persistent organ damage or impairment due to these diseases / disorders. For example, the compounds described herein can be used, in particular, to improve brain tissue damage or impairment following traumatic brain injury, or to improve brain tissue damage or impairment associated with Huntington's disease, Alzheimer's disease, ALS, and Niemann-Pick disease.

[0076] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof can be used to treat retinal detachment, macular degeneration, and retinitis pigmentosa, and to improve brain tissue damage or impairment caused by multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0077] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof may be used to treat Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondylitis, systemic paroxysmal juvenile idiopathic arthritis (SoJIA), and osteoarthritis.

[0078] In yet another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat psoriasis, rheumatoid arthritis, and ulcerative colitis.

[0079] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat lupus, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.

[0080] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof may be used to treat cerebrovascular accidents (CVA, stroke), Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.

[0081] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat amyotrophic lateral sclerosis (ALS).

[0082] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat multiple sclerosis.

[0083] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof can be used to treat pancreatic ductal adenocarcinoma (PDAC), metastatic tumors, melanoma, breast cancer, non-small cell lung cancer (NSCLC), and radiation-induced necrosis.

[0084] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat pancreatic ductal adenocarcinoma (PDAC), metastatic tumors, melanoma, breast cancer, and non-small cell lung cancer (NSCLC).

[0085] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat pancreatic ductal adenocarcinoma (PDAC).

[0086] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat intracerebral hemorrhage and subarachnoid hemorrhage.

[0087] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat type II diabetes and obesity.

[0088] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat atherosclerosis.

[0089] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat vasculitis.

[0090] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof can be used to treat dependent inflammation and cell death occurring in hereditary and sporadic diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis, and acute tissue damage caused by stroke, traumatic brain injury, or encephalitis.

[0091] In another embodiment, the compounds of the formula described herein or pharmaceutically acceptable salts thereof can be used to treat ischemic kidney injury, ocular ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0092] In another embodiment, the compound of the formula described herein or a pharmaceutically acceptable salt thereof may be used to treat non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).

[0093] The compounds of the present invention, especially those of the formula described herein or pharmaceutically acceptable salts thereof, can be used, in particular, to treat RIPK1-mediated cancer-related diseases or disorders. GongIn one aspect, humans possess solid tumors. In another aspect, tumors are selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung cancer (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In another aspect, humans possess one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung cancer, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In yet another aspect, humans possess liquid tumors such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphocytic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myeloid leukemia.

[0094] This disclosure also relates to a method for treating cancer or reducing the severity of cancer, said cancer being selected from: brain cancer (glioma), glioblastoma, astrocytoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, triple-negative breast cancer, inflammatory breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of the head and neck), kidney cancer, lung cancer (including squamous cell carcinoma of the lung, adenocarcinoma of the lung, small cell lung cancer and non-small cell lung cancer), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic carcinoma), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic... Myeloid leukemia, chronic neutrophilic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma Non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, lung cancer, vulvar cancer, cervical cancer, endometrial cancer, uterine cancer, kidney cancer (including clear cell renal carcinoma, papillary renal carcinoma, and renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), and testicular cancer.

[0095] Specific examples of clinical conditions based on hematologic malignancies include leukemia, such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; lymphomas, such as non-Hodgkin lymphoma and Hodgkin lymphoma; and so on.

[0096] The cancer can be any cancer in which there is an abnormal number of blast cells or unwanted cell proliferation, or any cancer diagnosed as a blood cancer, including lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myeloid cell or myeloid or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyeloid cell or promyeloid or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia, and megakaryocytic (or megakaryoblastic) leukemia. These leukemias can be collectively referred to as acute myeloid (or myeloid cell or myeloid) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), which include, but are not limited to, chronic myeloid (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include spinal dysplasia (or myelodysplastic syndrome or MDS), which can be called refractory anemia (RA), refractory anemia with blast excess (RAEB), and refractory anemia with blast excess (RAEBT); as well as myelofibrosis (MFS) with or without unexplained myeloid metaplasia.

[0097] Specific examples of clinical conditions based on hematologic malignancies include leukemias such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia; plasma cell malignancies such as multiple myeloma, MGUS, and Waldenström macroglobulinemia; lymphomas such as non-Hodgkin lymphoma and Hodgkin lymphoma; and so on. Hematopoietic system cancers also include lymphoid malignancies, which can affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extranodular sites. Lymphoid cancers include B-cell malignancies, including but not limited to B-cell non-Hodgkin lymphoma (B-NHL). B-NHL can be indolent (or low-grade), intermediate-grade (or aggressive), or high-grade (very aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including nodular MZL, extranodal MZL, splenic MZL, and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHL includes mantle cell lymphoma (MCL) with or without leukemia association, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHL includes Burkitt's lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-cell non-HL include immunoblastic lymphoma (or immunocytomas), primary exudative lymphoma, HIV-related (or AIDS-related) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenström macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocytic (LGL) leukemia, acute lymphoblastic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL can also include T-cell non-Hodgkin lymphoma (T-NHL) (including, but not limited to, unspecified (NOS) T-cell non-Hodgkin lymphoma), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disease (AILD), nasal natural killer (NK) cell / T-cell lymphoma, γ / δ lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sezary syndrome.

[0098] Cancers of the hematopoietic system also include Hodgkin lymphoma (or disease), which includes classical Hodgkin lymphoma, tuberous sclerotic Hodgkin lymphoma, mixed-cell Hodgkin lymphoma, lymphocyte-predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocytic depletion Hodgkin lymphoma. Cancers of the hematopoietic system also include plasma cell diseases or cancers such as multiple myeloma (MM), which includes smoldering MM, monoclonal gammopathy of undetermined significance (or unknown or unclear) (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Cancers of the hematopoietic system can also include other cancers of other hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. The tissues containing hematopoietic cells are referred to as “hematopoietic tissues” in this article, including bone marrow; peripheral blood; thymus and peripheral lymphoid tissues such as spleen, lymph nodes, mucosa-associated lymphoid tissues (e.g., intestinal-associated lymphoid tissue), tonsils, Peyer's patches and appendix, as well as other mucosa-associated lymphoid tissues such as bronchial endothelium.

[0099] Pharmaceutical Composition The compounds described herein can be administered orally or parenterally. When formulated into dosage forms suitable for administration, the compounds described herein can be used as pharmaceutical compositions for the prevention, treatment, or remedy of the aforementioned diseases.

[0100] In the clinical use of the compounds described herein, they are typically formulated into various dosage forms with pharmaceutically acceptable additives, and then administered. "Pharmaceutically acceptable" means that the additive, carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to the recipient. Therefore, a wide variety of additives commonly used in pharmaceutical formulations are available. Specific examples include gelatin, lactose, sucrose, titanium dioxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminum metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, dehydrated sorbitol fatty acid esters, polysorbates, sucrose fatty acid esters, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicate anhydride, talc, vegetable oils, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycols, cyclodextrin, hydroxypropyl cyclodextrin, etc.

[0101] Preparations formed using those additives include, for example, solid dosage forms such as tablets, capsules, granules, powders, and suppositories; and liquid dosage forms such as syrups, elixirs, and injections. These can be formulated according to conventional methods known in the field of pharmaceutical formulation. Liquid dosage forms can also be in a form that allows them to dissolve or suspend in water or any other suitable medium during use.

[0102] Especially for injectable preparations, if necessary, the preparation can be dissolved or suspended in physiological saline or glucose solution, and buffers or preservatives can be optionally added.

[0103] The pharmaceutical composition may contain 1 to 99.9% by weight, preferably 1 to 60% by weight, of the compound of the present invention. The composition may further contain any other therapeutically effective compound.

[0104] When the compounds of the present invention are used to prevent or treat the aforementioned diseases, the dosage and frequency of administration can vary according to the patient's sex, age, weight, disease condition, and the type and extent of the expected therapeutic effect. Generally, when administered orally, the dosage can be from 0.001 to 50 mg / kg body weight / day, and it can be administered once or in several divided doses. In specific embodiments, the dosage is from about 0.01 to about 25 mg / kg / day, and in particular embodiments, from about 0.05 to about 10 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets or capsules containing 0.01 mg to 1,000 mg. In specific implementations, the dosage is 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850, or 1,000 mg of the compound described herein. This dosage regimen may be adjusted to provide an optimal therapeutic response.

[0105] combination therapy The compounds of the present invention may be further used in combination with other therapeutic agents in methods for preventing or treating the aforementioned diseases, disorders and conditions.

[0106] The compounds of the present invention can be used in combination with one or more other drugs to treat, prevent, inhibit, or improve diseases or conditions to which the compounds described herein or other drugs may be useful, wherein the combination of drugs is safer or more effective than using each drug alone. Therefore, such other drugs can be administered simultaneously or sequentially with the compounds described herein or pharmaceutically acceptable salts thereof in amounts commonly used. When the compounds described herein are used simultaneously with one or more other drugs, the pharmaceutical composition may, in specific embodiments, contain such other drugs and the compounds described herein or pharmaceutically acceptable salts thereof in a unit dosage form. However, combination therapy may also include a therapy in which the compounds described herein or pharmaceutically acceptable salts thereof and one or more other drugs are administered at different overlapping schedules. It is also contemplated that, when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients may be used at lower doses than when each is used alone. Therefore, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds described herein or pharmaceutically acceptable salts thereof. Example

[0107] The following examples are intended to be illustrative and should not be construed as further limitations. The accompanying drawings referenced throughout this application, as well as all references, patents, and published patent applications, are expressly incorporated herein by reference.

[0108] abbreviation The abbreviations used in this article have the meanings listed below. Unless otherwise specified, abbreviations not listed below have their usual meanings.

[0109] General synthesis scheme General Synthesis Scheme I Starting with hydroxy acid I, chiral amino alcohol II or amino acetal III can be coupled to provide aldehyde IV upon oxidation or directly provide protected aldehyde V. Both IV and V are prepared for ring-closing cyclization under mild acidic conditions. Diastereomer mixtures can be separated using chiral SFC chromatography, or chiral hydroxy acids can be used to provide the desired (5') S ,7a' R Enantiomers. R can be aromatic, heteroaromatic or alkyl, while R1 can be a variety of functional groups or a versatile handle to further functionalize the ring system.

[0110] General Synthesis Scheme II For cases where the functional stem on the spiroring is an alcoholic hydroxyl group, the introduction of aromatic and heteroaromatic components can be widely carried out via the following methods: using Ar-X under conventional SNAr conditions, in a polar aprotic solvent (e.g., DMA or DMF), adding a base, and heating the mixture until the reaction is complete. Where SNAr chemistry is not feasible, the alcoholic hydroxyl group is converted into a leaving group for SN2 reaction with Ar-OH. Both methods can be applied in library formats.

[0111] General Synthesis Scheme III Extensive functionalization of benzyl ether spirocyclic compounds can be achieved via photoredox coupling of spirocyclic borate esters with Ar-X.

[0112] General Synthesis Scheme IV Palladium-catalyzed cross-coupling between alcohols and aryl halides can be used to obtain aryl ethers.

[0113] Synthesis of common intermediates Intermediates I-1, I-1-cis and I-1-trans 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (I-1) and (1s,3s)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (I-1-cis) and (1r,3r)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (I-1-trans) Step 1. 3-(benzyloxy)-1-((trimethyl)oxy)cyclobutane-1-carboxynitrile Zinc iodide (2 g, 6.27 mmol) was added to a solution of 3-(benzyloxy)cyclobutane-1-one (40 g, 227 mmol) and TMS-CN (59 g, 595 mmol) in DCM (300 ml) at 0 °C, and the resulting mixture was stirred at 20 °C for 12 h. New spots appeared on TLC. The reaction mixture was directly concentrated, and the residue was purified by rapid silica gel chromatography (ISCO®; 120 g SepaFlash® silica gel column, 5% ethyl acetate / petroleum ether gradient elution) to give 3-(benzyloxy)-1-((trimethyl)oxy)cyclobutane-1-carboxynitrile as a colorless oil. 1 H NMR (400 MHz, CDCl3-d) δ 7.29-7.39 (m, 5H), 4.45 (s, 2H), 3.90-4.03 (m, 1H), 3.01 (ddd, J= 2.8, 6.8, 9.6 Hz, 2H), 2.29-2.41 (m, 2H), 0.22-0.26 (m, 9H).

[0114] Step 2. Methyl 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid A solution of 46 g (167 mmol) of 3-(benzyloxy)-1-((trimethoxy)oxy)cyclobutane-1-carboxynitrile) in HCl / MeOH (4 M) (150 ml) and MeOH (150 ml) was stirred for 2 h at 60 °C. TLC and LCMS showed that the starting material had been consumed and the desired compound was found. The mixture was directly concentrated to give methyl 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid as a white solid, which was used directly for the next step without further purification. MS (ESI): m / z 237 [M+H] + .

[0115] Step 3. 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (racemic) (I-1) LiOH·H₂O (254 ml, 508 mmol) was added to a solution of methyl 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (40 g, 169 mmol) in MeOH (300 ml). The reaction mixture was stirred at 20 °C for 2 h. LC-MS showed that the starting material was consumed and the desired compound was found. The reaction solution was concentrated. The residue was dissolved in water (100 mL) and extracted with EtOAc (200 mL). The aqueous phase was acidified to pH ~2 with HCl (3 N) and extracted with EtOAc (200 ml x 3). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid as a colorless oil, which could be used directly for the next step without further purification. MS (ESI): m / z 223 [M+H] + . 1 H NMR (400 MHz, MeOD-d4)δ 7.21-7.41 (m, 5H), 4.42-4.46 (m, 2H), 3.99-4.35 (m, 1H), 2.49-2.88 (m, 2H), 2.15-2.38 (m, 2H).

[0116] Step 4. I-1-cis and I-1-trans 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (90 g, 405 mmol) was resolved by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm x 50 mm, 10 μm), conditions: n-heptane-EtOH (0.1% NH3·H2O)) to give (1s,3s)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (I-1-cis) as a yellow solid. t = 2.7, ee = 100%) and (1r,3r)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (I-1-trans) as a yellow oil t = 2.9, ee = 100%). MS(ESI): m / z 262 [M+H] + .

[0117] I-1-cis (peak 1) 1 H NMR (400 MHz, CD3OD -d4) δ 7.21-7.37 (m, 5H), 4.44 (s,2H), 4.09 (t, J = 6.8 Hz, 1H), 2.70-2.79 (m, 2H), 2.09-2.17 (m, 2H).

[0118] I-1-trans (peak 2) 1 H NMR (400 MHz, CD3OD -d4) δ 7.26-7.36 (m, 5H), 4.45 (s,2H), 4.34 (t, J = 7.2 Hz, 1H), 2.53-2.61 (m, 2H), 2.31 (ddd, J = 2.8, 7.2, 9.6Hz, 2H).

[0119] The compounds presented in Table 1 were prepared using procedures similar to those described above, following the synthetic route in intermediate I-1.

[0120] Table 1 .

[0121] Intermediate I-3 (S)-4-amino-4-(4-fluorophenyl)but-1-ol (I-3) Step 1. ( R , Z )- N-(4-Fluorobenzyl)-2-methylpropane-2-sulfinamide Add ( ) to the stirred mixture of 4-fluorobenzaldehyde (25 g, 201 mmol) in DCM (500 mL) R 2-Methylpropane-2-sulfinamide (29.3 g, 242 mmol) and Cs₂CO₃ (98 g, 302 mmol) were mixed and stirred at 20 °C for 12 h. LCMS showed the desired product. The mixture was filtered. Water (100 mL) was added to the mixture, and extraction was performed with DCM (100 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (ISCO®; 330 g SepaFlash® silica gel column, 30% EtOAc / petroleum ether gradient elution) to give ( ) as a yellow oil. R , Z )- N -(4-Fluorobenzyl)-2-methylpropane-2-sulfinamide. MS (ESI) m / z 228 [M+H] + . 1 H NMR (CDCl3-d, 400 MHz): δ 8.56 (s, 1H), 7.84-7.91 (m, 2H), 7.14-7.21 (m, 2H), 1.27 (s, 9H).

[0122] Step 2. R )- N -(( S 1-(4-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide Stirred at 0°C R,Z )- NZn (20.470 g, 313 mmol) and 3-bromoprop-1-ene (17.30 mL, 200 mmol) were added to a solution of (4-fluorobenzyl)-2-methylpropane-2-sulfinamide (35 g, 154 mmol), indium(III) trifluoromethanesulfonate (95 g, 169 mmol) in THF (500 mL). The mixture was then stirred at 20 °C under N2 for 16 h. LCMS and TLC (petroleum ether / EtOAc = 2:1) showed the desired mass was detected. The mixture was quenched with brine (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; Agela® rapid column silica gel-CS (220 g), 0-50% ethyl acetate / petroleum ether gradient elution) to give a yellow solid ( R )- N -(( S 1-(4-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide. MS (ESI) m / z 270 [M+H] + . 1 H NMR (CDCl3-d, 400 MHz): δ 7.28-7.33(m, 2H), 6.99-7.08 (m, 2H), 5.66-5.78 (m, 1H), 5.17-5.22 (m, 1H), 5.15 (s,1H), 4.52 (br t, J = 6.4 Hz, 1H), 3.79-4.00 (m, 1H), 2.54-2.63 (m, 1H), 2.44-2.54 (m, 1H), 1.19-1.24 (m, 9H).

[0123] Step 3. R )- N -(( S 1-(4-fluorophenyl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide Under N2 at -20℃ towards ( R )- N -(( S9-BBN (416 mL, 208 mmol) (0.5 M, in THF) was added dropwise to a solution of 1-(4-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (28 g, 104 mmol) in THF (300 mL). After the addition was complete, the reaction mixture was stirred at 20 °C for 16 h. Sodium perborate tetrahydrate (128 g, 832 mmol) and water (100 mL) were added to the reaction mixture and the mixture was stirred for another 3 h. LCMS showed that the starting material had been consumed and the desired compound was found. The reaction solution was extracted with EtOAc (200 mL x 3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (ISCO®; 220 g SepaFlash® silica gel rapid column, 100% EtOAc / petroleum ether gradient elution) to give a colorless oil. R )- N -(( S 1-(4-fluorophenyl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide. MS (ESI) m / z 288 [M+H] + . 1 H NMR (CDCl3-d, 400 MHz): δ 7.27-7.30(m, 2H), 7.00-7.06 (m, 2H), 4.41 (br t, J = 7.2 Hz, 1H), 3.58-3.69 (m, 2H), 1.86-1.94 (m, 2H), 1.46-1.55 (m, 2H), 1.16-1.22 (m, 9H).

[0124] Step 4. (S)-4-amino-4-(4-fluorophenyl)but-1-ol (I-3) Towards( R )- N -(( S (S)-4-amino-4-(4-fluorophenyl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide (15 g, 52.2 mmol) was added to a solution of MeOH (150 mL) in HCl / MeOH (4 M) (80 mL). The mixture was then stirred at 25 °C for 12 h. LC-MS showed the desired product mass. After completion, the mixture was concentrated under vacuum to give (S)-4-amino-4-(4-fluorophenyl)but-1-ol as a yellow oil. MS (ESI) m / z 184 [M+H] + .

[0125] The compounds presented in Table 2 were prepared using procedures similar to those described above, following the synthetic route in intermediate I-3.

[0126] Table 1 .

[0127] Intermediate I-14 (S)-3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl-1-amine Step 1. ( S 2-Methyl-N-(pyrazin-2-ylmethylene)propane-2-sulfinamide Add ( ) to a solution of pyrazine-2-carboxaldehyde (10 g, 93 mmol) in DCM (300 mL) at 25 °C. S 2-Methylpropane-2-sulfinamide (13.4 g, 111 mmol) and Cs₂CO₃ (90 g, 278 mmol) were mixed and stirred at 25 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a brown oil. The oil was purified by column chromatography (SiO₂, 330 g ISCO column, eluted with 10-70% EtOAc / hexane) to give ( S )-2-methyl- N -(pyrazin-2-ylmethylene)propane-2-sulfinamide. MS (ESI) m / z : 212 [M+H] + . 1 H NMR (CDCl3-d) δ: 9.27 (s, 1H), 8.77 (s, 1H), 8.75 - 8.71 (m, 1H), 8.69 (d, J = 2.1 Hz, 1H), 1.33 (s, 9H).

[0128] Step 2. S )- N -(( S )-3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-2-methylpropane-2-sulfinamide Under an inert atmosphere, 200 ml of 2-MeTHF (118 ml) was added to a 200 ml double-necked RBF container equipped with a 25 ml feeding funnel. S )-2-methyl- N-(pyrazin-2-ylmethylene)propane-2-sulfinamide (5.0 g, 23.7 mmol). The solution was cooled to -78 °C and treated dropwise with 0.5 M of ((2-(1,3-dioxane-2-yl)ethyl)magnesium bromide (49.7 mL, 24.9 mmol) in tetrahydrofuran over 10 min. The reaction mixture was heated to 0 °C over 4 h. The reaction mixture was quenched with aqueous ammonium chloride and heated to room temperature. The resulting mixture was transferred to a separatory funnel with ethyl acetate, the organic layer was cut and then washed with brine. The aqueous phase was backwashed twice with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The product was purified on an ISCO Gold-12 g silica gel column-0-100% [3:1 EtOAc:EtOH] / hexane to give (…) as an orange oil. S )- N -(( S )-3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-2-methylpropane-2-sulfinamide.

[0129] Step 3. S )-3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl-1-amine (I-14) Treatment of 2-MeTHF (17.6 mL) / water (4.4 mL) with iodine (419 mg, 1.650 mmol) at room temperature S )- N -(( S )-3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl)-2-methylpropane-2-sulfinamide (1081 mg, 3.3 mmol) for 20 hours. LCMS showed no starting material remaining. The reaction was quenched by adding 2.5 ml of ammonium hydroxide solution. After stirring for 2 hours, the aqueous layer was removed, THF was decanted into a recovery flask and concentrated. The aqueous layer was azeotropically removed to remove water, the residue was dissolved in acetonitrile and filtered into the first flask, and the combined organic matter was concentrated to give ( ) as a red oil. S 1,3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl-1-amine, which can be used directly without further purification. MS (ESI) m / z: 224 [M+H] + .

[0130] The compounds presented in Table 3 were prepared using procedures similar to those described above, based on the synthetic route in intermediate I-14.

[0131] Table 3 .

[0132] Intermediates I-18, I-18-trans and I-18-cis (5'S,7a'R)-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b] [Oxazol]-3'-one ( I-18 )and (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo] [2,1-b]oxazol]-3'-one ( I-18-Reverse )and (1s,3S,5'S,7a'R)-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo] [2,1-b]oxazol]-3'-one ( I-18-cis- ） Step 1. ( S )-3-(benzyloxy)- N -(1-(4-fluorophenyl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide Add TEA (22.82 mL, 164 mmol), HOBT (5.5 g, 36.0 mmol), EDCI (6.9 g, 36 mmol), and (…) to a stirred mixture of 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (8.0 g, 36 mmol) in DMF (150 mL). S (S)-3-(benzyloxy)-N-(1-(4-fluorophenyl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide as a yellow oil was obtained by LC-MS (ESI): 6.0 g, 33 mmol. The mixture was then stirred at 20 °C for 12 h. Water (200 mL) was added and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were concentrated, washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by rapid silica gel chromatography (ISCO®; 80 g SepaFlash® silica gel column, 10% EtOAc / petroleum ether gradient elution) to give (S)-3-(benzyloxy)-N-(1-(4-fluorophenyl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide as a yellow oil. MS (ESI): m / z 388 [M+H] + . 1H NMR (CDCl3-d, 400 MHz): δ 7.27-7.42 (m, 4H), 7.23-7.26 (m, 1H), 6.89-7.08 (m, 3H), 4.83-4.98 (m, 1H), 3.51-3.71 (m, 2H), 2.38-2.85 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.95 (m, 2H), 1.34-1.74 (m, 6H).

[0133] Step 2. S )-3-(benzyloxy)- N -(1-(4-fluorophenyl)-4-oxobutyl)-1-hydroxycyclobutane-1-carboxamide At 0℃ towards ( S )-3-(benzyloxy)- N 1-(1-(4-fluorophenyl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide (6 g, 15.49 mmol) was added to a solution of DMP (7.88 g, 18.58 mmol) in DCM (100 mL). The mixture was stirred at 20 °C for 1 h. LCMS showed that the starting material was consumed and the desired compound was found. Saturated NaHCO3 (70 mL) was added to the reaction mixture and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a crude product as a yellow oil. S )-3-(benzyloxy)- N -(1-(4-fluorophenyl)-4-oxobutyl)-1-hydroxycyclobutane-1-carboxamide. MS (ESI): m / z 386 [M+H] + .

[0134] Step 3. 5'S,7a'R )-3-(benzyloxy)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one At 80℃ ( S )-3-(benzyloxy)- N A mixture of 1-(4-fluorophenyl)-4-oxobutyl)-1-hydroxycyclobutane-1-carboxamide (6 g, 15.57 mmol) and MsOH (2.022 mL, 31.1 mmol) in MeCN (100 mL) was stirred for 2 h to obtain a yellow mixture. LC-MS showed detection of the desired MS. The mixture was concentrated under vacuum and subjected to rapid silica gel chromatography (ISCO). ® Agela ®Rapid column chromatography (80 g silica-CS, 20% ethyl acetate / petroleum ether gradient elution) was used to purify the product to obtain a yellow solid. 5'S,7a'R )-3-(benzyloxy)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 368 [M+H] + . 1 H NMR (CDCl3-d, 400 MHz): δ 7.28-7.37 (m, 5H), 7.19-7.25 (m, 2H), 6.99-7.06 (m, 2H), 5.55-5.66 (m, 1H), 4.98(q, J = 8.0 Hz, 1H), 4.44-4.49 (m, 2H), 4.10-4.38 (m, 1H), 2.54-2.93 (m, 3H), 2.30-2.49 (m, 2H), 2.15-2.26 (m, 1H), 1.93-2.04 (m, 1H), 1.63-1.76 (m, 1H).

[0135] Step 4. 5'S,7a'R )-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-18) At 20℃ towards ( 5'S,7a'R 3-(benzyloxy)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (2.8 g, 7.62 mmol) was added to a solution of Pd(OH)₂ (0.535 g, 0.762 mmol) and Pd / C (0.405 g, 0.762 mmol) in MeOH (60 mL). The mixture was stirred at 40 °C under H₂ for 16 h. TLC showed a new compound. The reaction solution was filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with 100% EtOAc and 20% EtOH / EtOAc) to give a yellow solid ( 5'S,7a'R )-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 278 [M+H] + . 1H NMR(CD3OD -d4, 400 MHz): δ 7.23-7.38 (m, 2H), 6.99-7.14 (m, 2H), 5.65-5.76 (m,1H), 4.91 (br t, J = 8.0 Hz, 1H), 4.07-4.49 (m, 1H), 2.78-2.78 (m, 1H), 2.54-2.88 (m, 2H), 2.31-2.48 (m, 1H), 2.15-2.30 (m, 2H), 1.89-2.02 (m, 1H), 1.57-1.69 (m, 1H).

[0136] Step 5. 1r,3R,5'S,7a'R )-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-18-trans) and ( 1s , 3S , 5'S , 7a'R )-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-18-cis) (5'S,7a'R)-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (1.8 g, 6.33 mmol) was separated by SFC column DAICEL CHIRALCEL IG (eluted with 0.1% NH3·H2O EtOH) to give a pale yellow solid. 5'S,7a'R )-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one and ( 5'S,7a'R )-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0137] trans (peak 1): 1 H NMR(CD3OD -d4, 400 MHz): δ 7.26-7.33 (m, 2H), 7.02-7.10(m, 2H), 5.70 (dd, J = 7.2, 5.2 Hz, 1H), 4.90-4.95 (m, 1H), 4.44 (t, J= 7.2 Hz,1H), 2.68-2.76 (m, 1H), 2.61-2.68 (m, 1H), 2.55-2.61 (m, 1H), 2.44 (br d, J =6.0 Hz, 1H), 2.26 (br dd, J = 12.4, 1.2 Hz, 2H), 1.92-2.03 (m, 1H), 1.63-1.74(m, 1H).

[0138] Trans (peak 2): 1 H NMR(CD3OD -d4, 400 MHz): δ 7.27-7.33 (m, 2H), 7.03-7.10(m, 2H), 5.71 (dd, J = 7.6, 4.8 Hz, 1H), 4.89-4.94 (m, 1H), 4.13 (quin, J = 7.2Hz, 1H), 2.79-2.87 (m, 2H), 2.66 (dtd, J = 13.2, 7.6, 2.4 Hz, 1H), 2.31-2.39(m, 1H), 2.17-2.25 (m, 2H), 1.95 (dddd, J = 13.2, 11.6, 8.0, 6.4 Hz, 1H), 1.63(tt, J = 12.0, 7.6 Hz, 1H).

[0139] The compounds presented in Table 4 were prepared using procedures similar to those described above, following the synthetic route in intermediate I-18.

[0140] Table 4 .

[0141] Intermediate I-28 (5'S,7a'R)-3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]) [Oxazol]-3'-one (I-28) Step 1. 1,3-Dihydroxycyclobutane-1-carboxylic acid At 20℃ towards ( 1R, 3R1,3-Dihydroxycyclobutane-1-carboxylic acid (5.6 g, 25.2 mmol) was added to a solution of 1,3-dihydroxycyclobutane-1-carboxylic acid in MeOH (100 mL) along with Pd(OH)₂ / C (1.8 g, 2.56 mmol) and Pd / C (1.4 g, 2.63 mmol). The mixture was stirred at 40 °C (50 psi) under H₂ for 16 h. The reaction was completed by TLC (petroleum ether / EtOAc 1:1). The mixture was filtered and evaporated under reduced pressure to give 1,3-dihydroxycyclobutane-1-carboxylic acid as a yellow solid. 1 H NMR (400 MHz, CD3OD -d4) δ 4.19 (quin, J =7.12 Hz, 1H), 2.83 (ddd, J =2.68, 7.21, 9.78Hz, 2H), 2.14 (ddd, J =2.68, 7.30, 9.69 Hz, 2H).

[0142] Step 2. S )- N -(3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-1,3-dihydroxycyclobutane-1-carboxamide Towards( S 1,3-Dihydroxycyclobutane-1-carboxylic acid (254 mg, 1.920 mmol), TEA (669 µl, 4.80 mmol), HOBT (368 mg, 2.400 mmol), and EDC (460 mg, 2.400 mmol) were added to a solution of 1,3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl-1-amine (357 mg, 1.6 mmol) in DMF (10.7 mL). The mixture was stirred at 20 °C for 12 h. LCMS showed that the desired compound was found. The mixture was filtered and the filtrate was purified by preparative HPLC (preparative HPLC conditions: preparative HPLC on a 245 g Gold ISOC RP (C18) column, using mobile phase AB: water (0.05% TFA)-ACN (0.05% TFA), gradient: 5-35%) to give a yellow oil. S )- N -(3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-1,3-dihydroxycyclobutane-1-carboxamide. MS (ESI): m / z 338[M+H] + .

[0143] Step 3. (5'S,7a'R)-3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-28) Towards( S )- N -(3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-1,3-dihydroxycyclobutane-1-carboxamide (467 mg, 1.384 mmol) was added to a solution in MeCN (6921 µl) with MsOH (270 µl, 4.15 mmol), and the mixture was stirred at 50 °C for 2 h. LC-MS showed that the starting material was consumed and the desired compound was found. The reaction mixture was filtered and then concentrated to give a crude residue, which was purified by MPLC: ISCO 24 g Gold column (eluted with [3:1 EtOAc:EtOH] / hexane (gradient 50-100%)) to obtain (5'S,7a'R)-3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1, 2'-pyrrolo[2,1-b]oxazol]-3'-one MS (ESI): m / z 262 [M+H] + .

[0144] The compounds presented in Table 5 below were prepared using procedures similar to those described above, following the synthetic route in intermediate I-28.

[0145] Table 5 .

[0146] Intermediate I-36 (1S,3S,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]) [Oxazolium]-3-ylmethanesulfonate Will( 1S,3S,5'S,7a'R A solution of 3-hydroxy-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (120 mg, 0.463 mmol) and triethylamine (129 µl, 0.926 mmol) in DCM (3085 µl) was cooled to 0 °C, and Ms-Cl (54.1 µl, 0.694 mmol) was added. The reaction solution was heated to room temperature, quenched with saturated sodium bicarbonate solution after 30 minutes, and extracted with DCM. The organic phase was washed with water, followed by brine, dried over sodium sulfate, filtered, and concentrated. Purification was performed via an ISCO silica gel 24 g Gold column (eluted with 10-60% [EtOAc / EtOH (3 / 1)] / hexane) to obtain ( 1S,3S,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3' H 3-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylmethanesulfonate. MS (ESI) m / z [M+H] + For C 16 H 19 INO5S calculated value: 337, measured value: 337.

[0147] Intermediate I-37 (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]ox ]-3,3'-dione At 0℃ towards ( 5'S,7a'R )-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3' H 1 g of spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (3.39 mmol) was added to a solution of DMP (2.155 g, 5.08 mmol) in DCM (20 mL), and the mixture was stirred at 20 °C for 12 h. LCMS showed that the starting material was consumed and the desired compound was found. Saturated NaHCO3 (20 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica gel column, 23% ethyl acetate / petroleum ether gradient elution) to give (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3,3'-dione as a colorless oil. MS (ESI) m / z [M+H] + For C 15 H 13 Calculated value of F2NO3: 294, Measured value: 294.

[0148] Intermediate I-38-cis (1s,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborane heterocycle) Pentane-2-yl)methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-38-cis) In a glove box, (1S,3S,5'S,7a'R)-3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-29-cis) (40 mg, 0.153 mmol), sodium hydride (4.90 mg, 0.184 mmol), and potassium fluoride (26.7 mg, 0.459 mmol) were added to a microwave-safe vial. The vial was sealed. Anhydrous THF was added under an inert atmosphere. The solution was allowed to stand for 30 min until hydrogen release had completely stopped. Then, pure 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (34.9 µl, 0.199 mmol) was added. Vigorous bubbling was observed. After another 10 minutes, the vial was irradiated in a microwave at 130°C for 40 min. The suspension was filtered through diatomaceous earth to obtain the crude product (1s,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one as a brown oil. This material was used immediately without further purification. MS (ESI) m / z [M-Pinalol + H₂O + H₂] + For C 14 H 18 BN3O5 calculated value: 320, measured value: 320.

[0149] The compounds presented in Table 6 below were prepared using a procedure similar to that described for I-38-cis, with appropriate intermediates selected from Table 5.

[0150] Table 6 .

[0151] 2-(4-Bromophenyl)-1,3,4-oxadiazole 4-Bromobenzoylhydrazide (90.0 g, 418 mmol, 1.00 eq) and trimethyl orthoformate (1310 g, 12.35 mol, 29.5 eq) were added to a 3.00 L three-necked round-bottom flask equipped with a magnetic stirrer at 25 °C, followed by the addition of TsOH (21.6 g, 125 mmol, 0.30 eq). The reaction mixture was stirred for 12 h at an internal temperature of 110 °C under a N2 atmosphere. The reaction mixture was then concentrated under vacuum to obtain the residue. It was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 2-(4-bromophenyl)-1,3,4-oxadiazole (70.0 g, 311.05 mmol, yield 74.32%). MS (ESI): m / z 224.9, 226.9 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ = 7.82 (d, J = 8.8 Hz, 2H), 7.95 (d, J =8.8 Hz, 2H), 9.36 (s, 1H).

[0152] Examples 1.1 and 1.2 ((1r or s),4R,5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrole] [2,1-b]oxazolium-3'-one and ((1s or r),4R,5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrole] [2,1-b]oxazolium-3'-one Step 1. (S)-1-Phenylacet-3-ene-1-amine dihydrochloride To a mixture of (R)-2-methyl-N-((S)-1-phenylbut-3-en-1-yl)propane-2-sulfinamide (1.07 g, 4.26 mmol, I-5) in MeOH (20 ml), HCl / MeOH (4 M) (5 ml) was added, and the mixture was stirred at 20 °C for 12 h. LC-MS showed that the starting material had been consumed and the desired compound was found. The reaction solution was directly concentrated to give (S)-1-phenylbut-3-en-1-amine dihydrochloride as a pale yellow solid, which was used directly for the next step without further purification. MS (ESI): m / z 148.3 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ 8.08 (br s, 2H), 7.45 (br d, J=7.09Hz, 2H), 7.28-7.37 (m, 3H), 5.43-5.63 (m, 1H), 4.96-5.16 (m, 2H), 4.29 (br s,1H), 2.68-2.95 (m, 2H).

[0153] Step 2. (S)-4-(benzyloxy)-1-hydroxy-N-(1-phenylbut-3-en-1-yl)cyclohexane-1-carboxamide TEA (0.668 mL, 4.79 mmol), HOBT (0.275 g, 1.80 mmol), EDC (0.35 g, 1.80 mmol), and (S)-1-phenylbut-3-ene-1-amine dihydrochloride (0.31 g, 1.32 mmol) were added to a solution of 4-(benzyloxy)-1-hydroxycyclohexane-1-carboxylic acid (0.3 g, 1.80 mmol) in DMF (6 mL) at 20 °C. The mixture was stirred at 20 °C. After 16 h, H2O (20 mL) was added to the mixture, and then the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 18% ethyl acetate / petroleum ether gradient elution) to give (S)-4-(benzyloxy)-1-hydroxy-N-(1-phenylbut-3-en-1-yl)cyclohexane-1-carboxamide as a yellow oil. MS (ESI): m / z 380 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ 7.28-7.32 (m, 5H), 7.14-7.26 (m, 5H), 5.56-5.74 (m, 1H), 4.94-5.08 (m, 3H), 4.53 (s, 2H), 3.30-3.46 (m, 1H), 2.58-2.60 (m, 1H), 2.46-2.60 (m, 1H), 1.83-2.01 (m, 4H), 1.45-1.71 (m, 4H).

[0154] Step 3. (S)-4-(benzyloxy)-1-hydroxy-N-(4-oxo-1-phenylbutyl)cyclohexane-1-carboxamide (S)-4-(benzyloxy)-1-hydroxy-N-(1-phenylbut-3-en-1-yl)cyclohexane-1-carboxamide (0.6 g, 1.58 mmol) was added to a mixture of silver nitrate (0.019 g, 0.13 mmol), copper(II) chloride (0.026 g, 0.19 mmol), and bis(benzonitrile)palladium dichloride (0.073 g, 0.19 mmol) stirred for 5 min at O2 and 20 °C in t-BuOH (20 mL) and MeNO2 (1.3 mL). The mixture was stirred at O2 and 20 °C for 16 h. The reaction mixture was then concentrated under vacuum to give the crude product (S)-4-(benzyloxy)-1-hydroxy-N-(4-oxo-1-phenylbutyryl)cyclohexane-1-carboxamide, which was used directly in the next step. MS (ESI): m / z 396. [M+H] + .

[0155] Step 4. (5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Methanesulfonic acid (0.44 g, 4.6 mmol) was added to a mixture of (S)-4-(benzyloxy)-1-hydroxy-N-(4-oxo-1-phenylbutyl)cyclohexane-1-carboxamide (0.6 g, 1.5 mmol) in CH3CN (8 mL) under stirring at 20 °C. The mixture was stirred at 80 °C for 2 h. The reaction mixture was then concentrated to give a crude product, which was purified by preparative-HPLC (column BostonGreen ODS 150 mm x 30 mm x 5 μm; conditions: water (TFA)-ACN) to give two diastereomers. MS (ESI): m / z 378 [M+H] + .

[0156] Example 1.1 (Peak 1): 1 H NMR (500 MHz, CD3OD -d4) δ 7.30-7.39 (m, 6H), 7.21-7.29 (m, 4H), 5.75 (dd, J = 5.0, 7.0 Hz, 1H), 4.95 (t, J = 7.5 Hz, 1H), 4.58 (s,2H), 3.48 (tt, J = 3.5, 10.0 Hz, 1H), 2.67 (dtd, J= 5.5, 8.0, 13.5 Hz, 1H),2.21-2.28 (m, 1H), 2.15 (qd, J = 3.5, 13.5 Hz, 1H), 1.95-2.10 (m, 3H), 1.57-1.88 (m, 6H).

[0157] Example 1.2 (Peak 2): 1 H NMR (500 MHz, CD3OD -d4) δ 7.20-7.44 (m, 10H), 5.75(dd, J = 5.5, 7.5 Hz, 1H), 4.96 (t, J = 8.0 Hz, 1H), 4.53 (s, 2H), 3.71 (br s,1H), 2.67 (dtd, J = 5.5, 8.0, 13.5 Hz, 1H), 2.16-2.28 (m, 2H), 1.93-2.05 (m,4H), 1.83-1.92 (m, 2H), 1.66-1.81 (m, 2H), 1.51 (br d, J = 13.5 Hz, 1H).

[0158] The compounds presented in Table 7 below were prepared using a procedure similar to that described for Examples 1.1 / 1.2, with appropriately selected intermediates.

[0159] Table 7 .

[0160] Examples 2.1 and 2.2 ((1r or s),4R,5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane] Alkyl-1,2'-pyrrolo[2,1-b]oxazol]-3'-one and ((1s or r),4R,5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane] [Alkyl-1,2'-pyrrolo[2,1-b]oxazol]-3'-one] Step 1. ( S )-4-(benzyloxy)- N -(1-(5-Fluoropyridin-3-yl)-4-hydroxybutyl)-1-hydroxycyclohexane-1-carboxamide TEA (2.23 mL, 16 mmol), HOBT (0.92 g, 5.99 mmol), EDC (1.15 g, 5.99 mmol), and (S)-4-amino-4-(5-fluoropyridin-3-yl)but-1-ol (0.88 g, 4.79 mmol, I-13) were added to a solution of 4-(benzyloxy)-1-hydroxycyclohexane-1-carboxylic acid (1 g, 4.00 mmol, I-2) in DMF (20 mL) at 20 °C. The mixture was stirred at 20 °C for 16 h. H2O (40 mL) was added to the mixture, followed by extraction with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica gel rapid column, 5% MeOH / DCM elution) to obtain a yellow oil. S )-4-(benzyloxy)- N -(1-(5-Fluoropyridin-3-yl)-4-hydroxybutyl)-1-hydroxycyclohexane-1-carboxamide. MS (ESI): m / z 417 [M+H] + . 1 H NMR (500 MHz, CDCl3-d) δ 8.33-8.44 (m, 2H), 7.28-7.46 (m, 6H), 4.94-5.04 (m, 1H), 4.45-4.60 (m, 2H), 3.39-3.80 (m, 3H), 1.85-2.05 (m, 7H), 1.65-1.82 (m, 2H), 1.51-1.63 (m, 4H).

[0161] Step 2. (S)-4-(benzyloxy)-N-(1-(5-fluoropyridin-3-yl)-4-oxobutyl)-1-hydroxycyclohexane-1-carboxamide At 0℃ towards ( S )-4-(benzyloxy)- N -(1-(5-fluoropyridin-3-yl)-4-hydroxybutyl)-1-hydroxycyclohexane-1-carboxamide (1.6 g, 3.7 mmol), pyridine (0.295 mL, 3.65 mmol) were added to a solution of DCM (25 mL), and DMP (3.10 g, 7.30 mmol) was added. The mixture was stirred at 20 °C. After 16 h, saturated NaHCO3 (40 mL) was added, and the reaction solution was extracted with DCM (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain a colorless oil. S)-4-(benzyloxy)- N -(1-(5-fluoropyridin-3-yl)-4-oxobutyl)-1-hydroxycyclohexane-1-carboxamide, which can be used directly in the next step without further purification. MS (ESI): m / z 415 [M+H] + .

[0162] Step 3. (5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Towards( S )-4-(benzyloxy)- N -(1-(5-fluoropyridin-3-yl)-4-oxobutyl)-1-hydroxycyclohexane-1-carboxamide (1.5 g, 3.6 mmol) was added to a mixture in acetonitrile (20 mL) with methanesulfonic acid (0.678 mL, 10.86 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction solution was then cooled, filtered, and the filtrate was purified by preparative HPLC (water (TFA)-ACN) to obtain two diastereomers. Peak 1 in Example 2.1 was a colorless oil. Peak 2 was further purified by preparative HPLC (NH3H2O+NH4HCO3)-ACN to obtain Example 2.2 as a colorless oil. MS (ESI): m / z 397 [M+H] + .

[0163] Example 2.1 (Peak 1): 1 H NMR (400 MHz, CD3OD -d4) δ 8.37-8.50 (m, 2H), 7.69(br d, J = 9.2 Hz, 1H), 7.22-7.38 (m, 5H), 5.77 (dd, J = 5.2, 7.6 Hz, 1H), 5.04(t, J = 8.0 Hz, 1H), 4.58 (s, 2H), 3.44-3.54 (m, 1H), 2.70-2.83 (m, 1H), 2.25-2.36 (m, 1H), 2.17-2.24 (m, 1H), 2.00-2.12 (m, 3H), 1.59-1.87 (m, 6H).

[0164] Example 2.2 (Peak 2): 1 H NMR (400 MHz, CD3OD -d4) δ 8.38 (d,J = 2.0 Hz, 2H),7.57-7.67 (m, 1H), 7.20-7.44 (m, 5H), 5.77 (dd, J = 4.8, 7.2 Hz, 1H), 5.03 (t, J = 8.0 Hz, 1H), 4.53 (s, 2H), 3.71 (br s, 1H), 2.70-2.80 (m, 1H), 2.15-2.32(m, 2H), 1.94-2.07 (m, 4H), 1.86-1.92 (m, 2H), 1.70-1.81 (m, 2H), 1.53 (br d, J = 13.2 Hz, 1H).

[0165] Example 3.1 (1s,3R,5'S,7a'R)-3-(benzyloxy)-5'-(5-fluoropyridin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1, 2'-pyrrolo[2,1-b]oxazol]-3'-one Step 1. (S)-3-(benzyloxy)-N-(1-(5-fluoropyridin-2-yl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide To the stirring ( S 4-Amino-4-(5-fluoropyridin-2-yl)but-1-ol (1.5 g, 8.14 mmol, I-10) was added to a mixture in DMF (40 mL) with TEA (1.14 mL, 8.14 mmol), 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (2.71 g, 12.2 mmol, I-1), HOBT (1.87 g, 12.2 mmol), and EDC (3.12 g, 16.3 mmol). The mixture was then stirred at 20 °C. After 12 h, water (300 mL) was added, and the mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were concentrated, washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by rapid silica gel chromatography (ISCO®; 220 g SepaFlash® silica gel column, 10% EtOAc / petroleum ether gradient elution) to obtain the yellow oil. S )-3-(benzyloxy)- N -(1-(5-Fluoropyridin-2-yl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide. MS (ESI) m / z 389 [M+H] + .1 H NMR (400 MHz, CDCl3-d) δ ppm1.45 - 1.57 (m, 2H) 1.80 - 1.92 (m, 2H) 2.09 (dd, J = 12.1, 6.3 Hz, 1H) 2.17 (dd, J = 12.1, 6.38 Hz, 1H) 2.49 - 2.58 (m, 1H) 2.74 - 2.81 (m, 1H) 2.84 (s,1H) 2.91 (s, 2H) 3.56 - 3.63 (m, 2 H) 4.04 - 4.12 (m, 1H) 4.36 - 4.42 (m, 2H)5.00 - 5.10 (m, 1H) 5.26 (s, 1H) 7.22 - 7.26 (m, 2H) 7.27 - 7.30 (m, 2H) 7.31- 7.38 (m, 2H) 7.89 (d, J = 8.5 Hz, 1H) 8.39 (d, J = 2.74 Hz, 1H).

[0166] Step 2. (S)-3-(benzyloxy)-N-(1-(5-fluoropyridin-2-yl)-4-oxobutyl)-1-hydroxycyclobutane-1-carboxamide At 0℃ towards ( S 3-(benzyloxy)-N-(1-(5-fluoropyridin-2-yl)-4-hydroxybutyl)-1-hydroxycyclobutane-1-carboxamide (500 mg, 1.29 mmol) was added to a solution of DCM (8 mL) with DMP (819 mg, 1.93 mmol), and the mixture was stirred at 20 °C. After 1 h, saturated NaHCO3 (15 mL) was added to the reaction mixture, and the mixture was extracted with DCM (10 mL x 2) and washed with brine (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain a yellow oil. S )-3-(benzyloxy)- N -(1-(5-Fluoropyridin-2-yl)-4-oxobutyl)-1-hydroxycyclobutane-1-carboxamide, which is used directly in the next step. MS (ESI): m / z 387 [M+H] + .

[0167] Step 3. (5'S,7a'R)-3-(benzyloxy)-5'-(5-fluoropyridin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Towards( S)-3-(benzyloxy)- N 1-(5-Fluoropyridin-2-yl)-4-oxobutyl)-1-hydroxycyclobutane-1-carboxamide (450 mg, 1.17 mmol) was added to a solution of p-toluenesulfonic acid monohydrate (55.4 mg, 0.29 mmol) in toluene (8 mL), and the mixture was stirred at 80 °C for 12 h. The mixture was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with NaSO4 (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; Agela® rapid column silica gel-CS (1 g), 0-5% ethyl acetate / petroleum ether gradient elution) to give two diastereomers of (5'S,7a'R)-3-(benzyloxy)-5'-(5-fluoropyridin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 369[M+H] + Example 3.1 (cis): 1 H NMR (500 MHz, CDCl3-d) δ 8.50 (d, J = 2.5 Hz, 1H), 7.48(dt, J = 2.5, 8.20 Hz, 1H), 7.38 (dd, J = 4.5, 8.5 Hz, 1H), 7.28 (d, J = 1.5 Hz,1H), 7.19-7.27 (m, 2H), 5.61 (dd, J = 5.0, 7.5 Hz, 1H), 5.01 (t, J = 7.5 Hz, 1H), 4.39 (s, 2H), 3.98 (t, J = 6.5 Hz, 1H), 2.74-2.87 (m, 2H), 2.64 (dtd, J = 2.5,8.0, 13.5 Hz, 1H), 2.38 (dd, J = 7.0, 11.0 Hz, 1H), 2.28 (dd, J = 7.0, 11.83 Hz, 1H), 2.17-2.24 (m, 1H), 2.04-2.15 (m, 1H), 1.57-1.70 (m, 1H).

[0168] Examples 4.1 and 4.2 ((1r),3R,5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-] Pyrrolo[2,1-b]oxazol]-3'-one ( Example 4.1 Trans )and ((1s),3R,5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-] Pyrrolo[2,1-b]oxazol]-3'-one ( Example 4.1 Cis ） Step 1. N -(3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxamide To a solution of 3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl-1-amine (700 mg, 3.14 mmol, I-14-S) in DMF (20 mL), 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (836 mg, 3.76 mmol, I-1), TEA (1.31 mL, 9.41 mmol), HOBT (720 mg, 4.70 mmol), and EDCI (902 mg, 4.70 mmol) were added, and the mixture was stirred at 20 °C for 6 h. Water (50 mL) was then added to the mixture, and extraction was performed using EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; Agela® rapid column silica gel-CS (20 g), 0-10% ethyl acetate / petroleum ether gradient elution) to obtain a yellow oil. N -(3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxamide. MS (ESI): m / z 428 [M+H] + .

[0169] Step 2. 3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Towards N-(3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl)-3-(benzyloxy)-1-hydroxycyclobutane-1-carboxamide (800 mg, 1.87 mmol) was added to a solution in MeCN (15 mL) with MsOH (0.122 mL, 1.87 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and concentrated, and the residue was purified by rapid silica gel chromatography (ISCO®; Agela® rapid column silica gel-CS (12 g), 0-10% ethyl acetate / petroleum ether gradient elution) to give crude 3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. The diastereomeric mixture of (5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (420 mg, 1.195 mmol) was separated by SFC (column DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm), conditions: 0.1% NH3·H2O EtOH) to give two diastereomeric isomers of (5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. Example 4.1 (peak 1 / trans) ee = 92%, t R =1.99 min and Example 4.2 (peak 2 / cis) ee=98.7%, t R =2.7 min, all in colorless oil. MS (ESI): m / z 352 [M+H] + .

[0170] Example 4.1 (Peak 1 / trans): 1 H NMR (CDCl3-d, 400 MHz): δ 8.67 (d, J = 1.2 Hz,1H), 8.49-8.56 (m, 2H), 7.27-7.38 (m, 5H), 5.63 (t, J = 5.6 Hz, 1H), 5.08-5.16(m, 1H), 4.42-4.51 (m, 2H), 4.33 (quin, J = 7.2 Hz, 1H), 2.80 (dd, J= 13.2, 7.6Hz, 1H), 2.61-2.68 (m, 1H), 2.53-2.60 (m, 1H), 2.39-2.47 (m, 2H), 2.24-2.34(m, 2H), 1.70-1.81 (m, 1H).

[0171] Example 4.2 (Peak 2 / cis): 1 H NMR (CDCl3-d, 400 MHz): δ 8.67 (s, 1H), 8.49-8.57 (m, 2H), 7.28-7.38 (m, 5H), 5.64-5.71 (m, 1H), 5.05-5.15 (m, 1H), 4.46(s, 2H), 4.07 (m, 1H), 2.79-2.94 (m, 2H), 2.56-2.66 (m, 1H), 2.43 (dd, J =11.6, 7.2 Hz, 1H), 2.24-2.38 (m, 3H), 1.67-1.77 (m, 1H).

[0172] Examples 5.1 and 5.2 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1, 2'-Pyrrolo[2,1-b]oxazolium-3-yl)oxy)pyrimidine-4-carboxylonitrile (Example 5.1) and 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1, 2'-Pyrrolo[2,1-b]oxazolium-3-yl)oxy)pyrimidine-4-carboxamide (Example 5.2) Step 1. (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxy-3-methyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one At -78℃ ( 5'S,7a'R5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3,3'-dione (100 mg, 0.34 mmol, I-37) was added to a solution of methyl magnesium bromide (0.23 mL, 0.68 mmol) in THF (2 mL), and the reaction mixture was stirred at -78 °C for 2 h. The mixture was then added to saturated NH4Cl (5 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Boston Uni C18 [150 mm × 40 mm × 5 µm]; 35–65% water [0.01% TFA] / MeCN) to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxy-3-methyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one as a white solid. MS (ESI) m / z [M+H] + For C 16 H 17 Calculated value of F2NO3: 310, Measured value: 310.

[0173] Step 2. 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile and 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxamide NaH (2.59 mg, 0.065 mmol) was added to a solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxy-3-methyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (10 mg, 0.032 mmol) in THF (1 mL) at 0 °C. The mixture was stirred at 0 °C for 5 min. Then 6-chloropyrimidin-4-carboxynitrile (6.77 mg, 0.048 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to obtain a residue, which was purified by preparative HPLC (C18; 50-80% water [0.05% NH3H2O ​​+ 10 mM NH4HCO3] / MeCN) to give 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile (Example 5.1) and 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxamide (Example 5.2).

[0174] Example 5.1: 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 1.2 Hz, 1H), 7.05 (d, J =1.2 Hz, 1H), 6.59-6.88 (m, 3H), 5.62 (dd, J = 5.6 Hz, 1H), 4.96 (t, J = 7.6 Hz, 1H), 3.20 (br d, J = 13.6 Hz, 1H), 2.88-2.97 (m, 1H), 2.73-2.81 (m, 1H), 2.51-2.65 (m, 2H), 2.19-2.28 (m, 1H), 1.93-2.03 (m, 1H), 1.86 (s, 3H), 1.69-1.78(m, 1H). MS(ESI) m / z [M+H] + For C 21 H 18 Calculated value of F2N4O3: 413, Measured value: 413.

[0175] Example 5.2:1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 1.2 Hz, 1H), 7.73 (brs, 1H), 7.47 (d, J = 1.6 Hz, 1H), 6.61-6.83 (m, 3H), 5.54-5.70 (m, 2H), 4.96(t, J = 7.6 Hz, 1H), 3.22 (br d, J = 13.2 Hz, 1H), 2.94 (br d, J = 13.6 Hz, 1H), 2.72-2.82 (m, 1H), 2.51-2.65 (m, 2H), 2.18-2.30 (m, 1H), 1.93-2.02 (m, 1H), 1.86 (s, 3H), 1.70-1.78 (m, 1H). MS(ESI) m / z [M+H] + For C 21 H 20 Calculated value of F2N4O4: 431, measured value: 431.

[0176] Examples 6.1, 6.2, 6.3, and 6.4 6-((((1r or s),3R,5'(S or R),7a'R)-5'-(1-methyl-1H-pyrazole-4-yl)-3'-oxotetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile and 6-((((1s or r),3R,5'(S or R),7a'R)-5'-(1-methyl-1H-pyrazole-4-yl)-3'-oxotetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile and 6-((((1r or s),3R,5'(R or S),7a'R)-5'-(1-methyl-1H-pyrazole-4-yl)-3'-oxotetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile and 6-((((1s or r),3R,5'(R or S),7a'R)-5'-(1-methyl-1H-pyrazole-4-yl)-3'-oxotetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile Step 1. Methyl 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid TMS-diazomethane (27.0 mL, 54.0 mmol) was added to a mixture of 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (6.0 g, 27.0 mmol) in DCM (100 mL) and MeOH (30 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was then concentrated to give methyl 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid, which could be used directly without further purification. 1H NMR (CDCl3-d, 400 MHz): δ 7.27-7.38 (m, 5H), 4.46 (d, J = 1.2 Hz,2H), 3.99-4.44 (m, 1H), 3.76-3.89 (m, 3H), 2.83 (ddd, J = 10.0, 6.8, 3.2 Hz,1H), 2.58-2.67 (m, 1H), 2.33-2.47 (m, 2H).

[0177] Step 2. 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxamide A solution of methyl 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (6.2 g, 26.2 mmol) in NH3·MeOH (7 M) (100 mL) was stirred for 12 h at 50 °C. Afterward, the mixture was concentrated under vacuum to obtain crude 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxamide, which could be used directly without further purification. MS (ESI): m / z 221 [M+H] + .

[0178] Step 3. 3-(benzyloxy)-5'-methoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one To a solution of 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxamide (4.5 g, 20.3 mmol) in MeCN (100 mL), 2,5-dimethoxytetrahydrofuran (3.36 g, 25.4 mmol) and 4-methylbenzenesulfonic acid hydrate (0.387 g, 2.03 mmol) were added, and the mixture was stirred at 40 °C for 12 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (ISCO®; Agela® rapid column silica gel-CS (4 g), 0-10% ethyl acetate / petroleum ether gradient elution) to give 3-(benzyloxy)-5'-methoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 303 [M+H] + . 1H NMR (CDCl3-d, 400 MHz): δ 7.28-7.36(m, 5H), 5.46-5.58 (m, 1H), 5.00-5.08 (m, 1H), 4.44-4.48 (m, 2H), 4.00-4.35(m, 1H), 3.41 (d, J = 1.2 Hz, 3H), 2.78-2.84 (m, 1H), 2.57-2.77 (m, 1H), 2.37-2.44 (m, 1H), 2.36 (s, 3H), 1.88-1.99 (m, 1H), 1.61-1.72 (m, 1H).

[0179] Step 4. 3-(benzyloxy)-7',7a'-dihydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one TMSOTf (2.54 mL, 14.8 mmol) was slowly added to a DCM (60 mL) solution of 3-(benzyloxy)-5'-methoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (3.0 g, 9.9 mmol) and DIPEA (3.27 mL, 19.8 mmol) at 0 °C. The mixture was then stirred at 20 °C for 3 h. The reaction mixture was quenched by adding water (50 mL) and extracted with DCM (50 mL x 3). The combined organic fractions were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO®; Agela® rapid column silica gel-CS (12 g), 0-10% ethyl acetate / petroleum ether gradient elution) to give 3-(benzyloxy)-7',7a'-dihydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 272 [M+H] + . 1 H NMR (CDCl3-d, 400 MHz): δ 7.34-7.36 (m, 4H), 7.29-7.32 (m, 1H), 6.46 (td, J = 4.0, 2.0 Hz, 1H), 5.80-5.95 (m, 1H), 5.33-5.38 (m, 1H), 4.46 (d, J= 3.6 Hz, 2H), 4.27-4.36 (m, 1H), 2.56-2.72 (m, 3H), 2.28-2.46 (m, 3H).

[0180] Step 5. 3-(benzyloxy)-5'-(1-methyl-1H-pyrazole-4-yl)-5',7a'-dihydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one To a solution of 3-(benzyloxy)-7',7a'-dihydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (200 mg, 0.74 mmol) in DMF (6 mL), 4-iodo-1-methyl-1H-pyrazole (307 mg, 1.47 mmol), Ag₂CO₃ (407 mg, 1.47 mmol), and Pd(dppf)Cl₂ (108 mg, 0.15 mmol) were added, and the mixture was stirred at 120 °C under N₂ for 12 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150 x 25 mm x 5 μm; conditions: water (0.01% TFA)-MeCN) to give 3-(benzyloxy)-5'-(1-methyl-1H-pyrazole-4-yl)-5',7a'-dihydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 352 [M+H].

[0181] Step 6. 3-Hydroxy-5'-(1-methyl-1H-pyrazole-4-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Pd(OH)₂ / C (11.99 mg, 0.017 mmol) and Pd / C (9.09 mg, 0.017 mmol) were added to a solution of 3-(benzyloxy)-5'-(1-methyl-1H-pyrazol-4-yl)-5',7a'-dihydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (60 mg, 0.17 mmol) in MeOH (5 mL) at 20 °C. The mixture was stirred at 40 °C under H₂ for 16 h. The mixture was filtered and evaporated under reduced pressure to give 3-hydroxy-5'-(1-methyl-1H-pyrazol-4-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 264 [M+H] + .

[0182] Step 7. 6-((5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile NaH (9 mg, 0.23 mmol) was added to a solution of 3-hydroxy-5'-(1-methyl-1H-pyrazol-4-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (30 mg, 0.114 mmol) in THF (1 mL) at 0 °C and stirred for 10 min. Then 6-chloropyrimidin-4-carboxynitrile (234 mg, 0.17 mmol) was added, and the mixture was stirred at 20 °C for 2 h. MeCN (1 mL) was then added to the reaction mixture, filtered, concentrated under vacuum, and purified by preparative reversed-phase HPLC (column Welch Xtimate C18 150 x 25 mm x 5 μm; conditions: water (10 mM NH4HCO3)-MeCN) to give 6-((5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile. MS (ESI): m / z 367 [M+H] + .

[0183] Step 8. Chiral resolution of the diastereomeric derivatives of 6-((5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxylon Four diastereomers of 6-((5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxylonitrile (15 mg, 0.041 mmol) were purified as a white solid by a preparative SFC column (Phenomenex-Cellulose-2 (250 mm x 50 mm, 10 μm); conditions: 0.1% NH3·H2O EtOH). m / z 367 [M+H] + .

[0184] Example 6.1 Peak 1 (RT = 2.91 min, ee = 99%) First trans isomer: 1 H NMR (400MHz, CDCl3-d): δ 8.81 (d, J = 0.8 Hz, 1H), 7.39 (d, J = 9.6 Hz, 2H), 7.11 (d, J = 0.8Hz,1H), 5.43-5.62 (m, 2H), 4.97 (t, J = 7.2 Hz, 1H), 3.80-3.92 (m, 3H), 2.87-3.01(m, 2H), 2.67-2.76 (m, 1H), 2.62 (m, 1H), 2.47-2.57 (m, 1H), 2.22-2.30 (m,1H), 2.08-2.17 (m, 1H), 1.71-1.78 (m, 1H).

[0185] Example 6.2 Peak 2 (RT=4.19 min, ee = 92%) First cis isomer: 1 H NMR (400MHz, CDCl3-d): δ 8.81 (s, 1H), 7.39 (d, J = 10.0 Hz, 2H), 7.08 (s, 1H), 5.57 (dd, J =6.8, 5.2 Hz, 1H), 5.17-5.34 (m, 1H), 4.98 (t, J= 7.6 Hz, 1H), 3.88 (s, 3H), 3.05-3.23 (m, 2H), 2.46-2.60 (m, 3H), 2.21-2.29 (m, 1H), 2.07-2.15 (m, 1H), 1.68-1.72 (m, 1H).

[0186] Example 6.3 Peak 3 (RT = 5.00 min, ee = 95%) Second trans isomer: 1 H NMR (400MHz, CDCl3-d): δ 8.81 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 9.6 Hz, 2H), 7.11 (d, J = 1.1Hz, 1H), 5.42-5.60 (m, 2H), 4.97 (t, J = 7.2 Hz, 1H), 3.80-3.95 (m, 3H), 2.88-3.00 (m, 2H), 2.68-2.75 (m, 1H), 2.62 (dd, J = 13.2, 6.8 Hz, 1H), 2.48-2.56 (m,1H), 2.22-2.30 (m, 1H), 2.07-2.16 (m, 1H), 1.67-1.78 (m, 1H).

[0187] Example 6.4 Peak 4 (RT = 5.62 min, ee = 79%) Second cis isomer: 1 H NMR (400MHz, CDCl3-d): δ 8.81 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 10.0 Hz, 2H), 7.08 (d, J = 1.2Hz, 1H), 5.57 (dd, J = 6.8, 5.2 Hz, 1H), 5.25 (quin, J = 7.2 Hz, 1H), 4.98 (t, J =7.6 Hz, 1H), 3.88 (s, 3H), 3.04-3.23 (m, 2H), 2.45-2.64 (m, 3H), 2.20-2.31(m, 1H), 2.05-2.18 (m, 1H), 1.67-1.74 (m, 1H).

[0188] Examples 7.1 and 7.2 (1r,3R,5'S,7a'R)-3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-] 1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 7.1) (1s,3S,5'S,7a'R)-3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-] 1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 7.2) Step 1. 1-(3-(benzyloxy)cyclobutoxy)-2,4-difluorobenzene DIAD (0.874 mL, 4.50 mmol) was added to a solution of 3-(benzyloxy)cyclobut-1-ol (822 mg, 4.61 mmol), 2,4-difluorophenol (500 mg, 3.84 mmol), and Ph3P (1.21 g, 4.6 mmol) in THF (15 mL) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was directly purified by rapid silica gel chromatography (ISCO®; 20 g SepaFlash® silica gel column, 3% ethyl acetate / petroleum ether gradient elution) to give 1-(3-(benzyloxy)cyclobutoxy)-2,4-difluorobenzene. 1 H NMR (400 MHz, CD3OD -d4) δ 7.24-7.38 (m, 5H), 6.79-7.00 (m, 3H), 4.83-4.86 (m, 1H), 4.45 (s, 2H), 4.34 (m, 1H), 2.33-2.55(m, 4H).

[0189] Step 2. 3-(2,4-Difluorophenoxy)cyclobut-1-ol Pd / C (275 mg, 0.26 mmol) (10%, in activated carbon) and dihydroxypalladium (181 mg, 0.258 mmol) were added to a solution of 1-(3-(benzyloxy)cyclobutoxy)-2,4-difluorobenzene (750 mg, 2.58 mmol) in MeOH (15 mL) at 20 °C under H2 (15 psi). The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give 3-(2,4-difluorophenoxy)cyclobut-1-ol, which could be used directly without further purification. 1 H NMR (400 MHz, CD3OD -d4) δ 6.80-7.01 (m, 3H), 4.82-4.85 (m, 1H), 4.51 (tt, J= 5.2, 7.2 Hz,1H), 2.41-2.49 (m, 2H), 2.30-2.39 (m, 2H).

[0190] Step 3. 3-(2,4-Difluorophenoxy)cyclobut-1-one DMP (1589 mg, 3.75 mmol) was added to a solution of 3-(2,4-difluorophenoxy)cyclobut-1-ol (500 mg, 2.5 mmol) in DCM (15 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was added to saturated NaHCO3 (10 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 10% ethyl acetate / petroleum ether gradient elution) to give 3-(2,4-difluorophenoxy)cyclobut-1-one. 1 H NMR (400MHz, CDCl3-d) δ 6.76-6.96 (m, 3H), 5.00 (m, 1H), 3.43-3.54 (m, 2H), 3.30-3.41(m, 2H).

[0191] Step 4. 3-(2,4-Difluorophenoxy)-1-((trimethylsilyl)oxy)cyclobutane-1-carboxynitrile Zinc(II) iodide (24 mg, 0.08 mmol) was added to a solution of 3-(2,4-difluorophenoxy)cyclobut-1-one (500 mg, 2.5 mmol) and TMSCN (751 mg, 7.6 mmol) in DCM (15 mL) at 0 °C. The reaction mixture was stirred at 25 °C under N2 for 12 h. The reaction mixture was directly concentrated, and the residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 4% ethyl acetate / petroleum ether gradient elution) to give 3-(2,4-difluorophenoxy)-1-((trimethylsilyl)oxy)cyclobutane-1-carboxynitrile. MS (ESI): m / z 298 [M+H] + . 1 H NMR(400 MHz, CDCl3-d) δ 6.85-6.93 (m, 1H), 6.74-6.84 (m, 2H), 4.48-4.91 (m, 1H), 2.85-3.28(m, 2H), 2.56-2.84 (m, 2H), 0.25-0.29 (m, 9H).

[0192] Step 5. Methyl 3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxylic acid To a solution of 3-(2,4-difluorophenoxy)-1-((trimethylsilyl)oxy)cyclobutane-1-carboxynitrile (300 mg, 1.009 mmol) in MeOH (4 mL), HCl / MeOH (4 M) (4 mL) was added, and the reaction mixture was stirred at 60 °C for 2 h. The mixture was then directly concentrated to give methyl 3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxylic acid, which was used directly for the next step without further purification. MS (ESI): m / z 258 [M+H] + .

[0193] Step 6. 3-(2,4-Difluorophenoxy)-1-hydroxycyclobutane-1-carboxylic acid LiOH·H₂O (117 mg, 2.8 mmol) was added to a solution of methyl 3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxylic acid (240 mg, 0.93 mmol) in MeOH (5 mL) and water (0.5 mL). The reaction mixture was stirred at 25 °C for 4 h, after which the reaction mixture was concentrated, and the residue was dissolved in water (10 mL) and extracted with EtOAc (1 x 3 mL). The aqueous phase was acidified to pH ~4 with 2 N HCl (0.5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give 3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxylic acid, which was used directly for the next step without further purification. 1 H NMR (400 MHz, CDCl3-d) δ 6.67-6.97 (m, 3H), 4.61-5.06 (m, 1H), 2.88-3.16 (m, 2H), 2.58-2.75 (m, 2H).

[0194] Step 7. N -(3-(1,3-dioxane-2-yl)-1-(pyrazin-2-yl)propyl)-3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxamide To a solution of 3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl-1-amine (80 mg, 0.36 mmol, I-14) in DMF (5 mL), 3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxylic acid (80 mg, 0.33 mmol), TEA (0.150 mL, 1.08 mmol), HOBT (82.0 mg, 0.537 mmol), and EDC (103 mg, 0.54 mmol) were added, and the mixture was stirred at 20 °C for 3 h. The mixture was then added to water (30 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to give N-(3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl)-3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxamide, which was used directly in the next step without further purification. MS (ESI): m / z 450 [M+H] + .

[0195] Step 8. 3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one MeSH (0.029 mL, 0.45 mmol) was added to a solution of N-(3-(1,3-dioxan-2-yl)-1-(pyrazin-2-yl)propyl)-3-(2,4-difluorophenoxy)-1-hydroxycyclobutane-1-carboxamide (100 mg, 0.22 mmol) in MeCN (4 mL), and the mixture was stirred at 80 °C to obtain mixture 2. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (preparative HPLC conditions: using mobile phase AB: water (0.1% TFA)-ACN on an EB instrument equipped with a Boston Prime C18 150x40mmx5μm, gradient: 45-65%) to give 3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI): m / z 374 [M+H] + .

[0196] Step 9. Separation of diastereomers Two diastereomers of 3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (60 mg, 0.161 mmol) were resolved by chiral SFC (instrument SFC-21, method column DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 μm), 0.1% NH3H2O ​​ETOH). Example 7.1 (peak 1, trans) (Rt = 1.17 min, ee = 100%) and Example 7.2 (peak 2, cis) (Rt = 1.78 min, ee = 100%).

[0197] Example 7.1 (Peak 1, trans): 1 H NMR (400 MHz, CDCl3-d) δ 8.68 (s, 1H), 8.53 (m,2H), 6.71-6.92 (m, 3H), 5.65-5.72 (m, 12H), 5.14 (dd, J = 6.0, 7.6 Hz, 1H), 4.90 (m, 1H), 3.01 (dd, J = 7.6, 13.6 Hz, 1H), 2.86 (td, J = 6.4, 13.2 Hz, 1H), 2.55-2.71 (m, 3H), 2.26-2.38 (m, 2H), 1.72-1.86 (m, 1H).

[0198] Example 7.2 (Peak 2, cis): 1 H NMR (400 MHz, CDCl3-d) δ 8.67 (d, J = 0.8 Hz,1H), 8.49-8.56 (m, 2H), 6.68-6.92 (m, 3H), 5.70 (dd, J = 4.8, 7.2 Hz, 1H),5.05-5.16 (m, 1H), 4.60 (m, 1H), 2.97-3.13 (m, 2H), 2.52-2.69 (m, 3H), 2.24-2.38 (m, 2H), 1.64-1.79 (m, 1H).

[0199] Example 8.1 2-Fluoro-4-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrole] [2,1-b]oxazolium-3-yl)oxybenzylnitrile 2-Fluoro-4-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)benzylnitrile Micro-library preparation: A solution of 0.2 M (1s,3S,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylmethanesulfonate (I-36) (150 mg, in 2.1 mL DMSO) was prepared, and then 12 µl (0.0025 mmol) was injected into the wells containing cesium carbonate (1.6 mg, 0.005 mmol). A 0.35 M solution of 2-fluoro-4-hydroxybenzyl nitrile in DMSO was prepared separately and then injected into the wells (12.5 µl, 0.0044 mmol). The wells were sealed and heated to 80 °C overnight. After cooling, the reaction solution was diluted to 0.100 ml, filtered, and purified by RP-HPLC (method: TFA modified, 35% to 70% ACN in H2O) to give 2-fluoro-4-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)benzylnitrile. MS (ESI) m / z [M+H] + For C 22 H 19 Calculated value of FN2O3: 378, measured value: 378.

[0200] The compounds presented in Table 8 below were prepared using a procedure similar to that described for Example 8.1, with appropriately selected commercially available aromatic alcohols. Unless otherwise stated, all products are in the trans configuration.

[0201] Table 8 .

[0202] Example 9.1 6-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyridine] [2,1-b]oxazolium-3-yl)oxy)pyrimidin-4-carboxynitrile 6-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile NaH (3.2 mg, 0.081 mmol) was added to a solution of (5'S,7a'R)-5'-(4-fluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-18-trans) (15 mg, 0.054 mmol) in THF (1 mL) at 0 °C and stirred for 20 min. Then 6-chloropyrimidin-4-carboxynitrile (11.3 mg, 0.081 mmol) was added, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by adding water (1 mL) and extracted with EtOAc (3 × 1 mL). The organic layer was concentrated and purified by preparative HPLC (column Welch Xtimate C18 150 x 25 mm x 5 μm; conditions: water (10 mM-NH4HCO3)-ACN) to give 6-(((5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile as a colorless oil. MS (ESI): m / z 403 [M+Na] + . 1 H NMR (CDCl3-d, 400 MHz): δ 8.82 (d, J = 1.0 Hz, 1H), 7.21-7.25 (m, 2H), 7.11 (d, J = 1.0 Hz, 1H), 7.00-7.07 (m, 2H), 5.64 (dd, J =6.5, 5.3 Hz, 1H), 5.53 (m, 1H), 5.00 (t, J = 7.5 Hz, 1H), 2.92-3.02 (m, 2H), 2.65-2.78 (m, 2H), 2.56-2.64 (m, 1H), 2.21-2.29 (m, 1H), 2.03 (m, 1H), 1.69-1.79 (m, 1H).

[0203] Examples 9.2 and 9.3 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrole] [2,1-b]oxazolium-3-yl)oxy)pyrimidine-4-carboxynitrile (5'S,7a'R)-3-((6-chloropyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane] [Alkyl-1,2'-pyrrolo[2,1-b]oxazol]-3'-one] (5'S,7a'S)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (15 mg, 0.05 mmol) (I-20-trans), DMSO (1 mL), and 6-chloropyrimidin-4-carboxynitrile (14.1 mg, 0.102 mmol) were purged with nitrogen for 1 min, followed by the addition of sodium tert-butoxide (0.051 mL, 0.102 mmol). The resulting reaction mixture was heated overnight at 90 °C in a sealed reaction vessel. The crude product was purified by reversed-phase chromatography (eluting with acetonitrile / water + 0.05% TFA). The solid obtained by further purification by preparative TLC (silica gel) (developed with an EtOAc / hexane mixture (20% ethyl acetate v / v)) yielded 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile (Example 9.2) MS (ESI) m / z [M+H] + : 399. 1 H NMR (500 MHz, CDCl3- d ) δ 8.84 (s, 1H), 7.13 (s, 1H), 6.80(d, J = 6.1 Hz, 2H), 6.74 (t, J = 8.6 Hz, 1H), 5.64 (s, 1H), 5.59-5.52 (m,1H), 5.00 (t, J = 6.9 Hz, 1H), 3.05-2.96 (m, 2H), 2.80-2.69 (m, 2H), 2.68-2.59 (m, 1H), 2.31-2.23 (m, 1H), 2.04 (d, J = 18.7 Hz, 1H), 1.78 (d, J = 10.1Hz, 1H), and (5'S,7a'R)-3-((6-chloropyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 9.3). MS (ESI) m / z [M+H] + 408, 1 H NMR (500 MHz, CDCl3-) d) δ 8.58 (s, 1H), 6.80 (d, J = 7.4 Hz, 3H), 6.73 (t, J = 8.6Hz, 1H), 5.64 (s, 1H), 5.56-5.48 (m, 1H), 4.99 (d, J = 7.1 Hz, 1H), 2.98 (s,2H), 2.77-2.66 (m, 2H), 2.66-2.58 (m, 1H), 2.25 (s, 1H), 2.01 (s, 1H), 1.76(s, 1H).

[0204] The compounds presented in Table 9 below were prepared using a procedure similar to that described for Examples 9.1, 9.2, or 9.3, using suitable intermediates selected from Table 4, along with suitable solvents, bases, and commercially available or known electrophiles. Unless otherwise known, all products are in cis or trans configurations, with the elution order designated as peak 1 or peak 2.

[0205] Table 9 .

[0206] Example 9.46 (1r,3R,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy) Tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one K3PO4 (3.8 g, 17.91 mmol) was added to a dried 250 mL RBF container inside a glove box. The flask was sealed. A solution of (1r,3R,5'S,7a'R)-3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one I-30 (3.6 g, 13.78 mmol) and 4-chloropyrrolo[2,1-f][1,2,4]triazine (3174 mg, 20.67 mmol) in tert-butanol (68.9 mL, 13.78 mmol) was added. The resulting solution was heated to 70 °C and maintained for 7 h. After completion was determined by LCMS, the reaction mixture was cooled to 20 °C and quenched with NH4Cl / EtOAc (75 mL). The contents of the flask were vigorously stirred until all residues dissolved, and transferred to a separatory funnel, partitioned between EtOAc (300 mL) and a saturated aqueous solution of NH4Cl (300 mL). The phases were separated, and the organic layer was washed with brine (200 mL). The combined aqueous layer was backwashed twice with EtOAc (100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was dissolved in 5V IPAc at 50 °C, followed by the addition of 5V heptane. The solution was cooled to 35 °C and stirred for 3 h. The solid was filtered off, washed with cold IPAc, and then with heptane. (1r,3R,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one was obtained. MS(ESI) m / z [M+H] + C 19 H 18 N6O3: 379. 1H NMR(499 MHz, DMSO) δ 8.73 (s, 1H), 8.64 (s,1H), 8.61 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 6.88 (dd, J = 4.4,1.4 Hz, 1H), 6.85 (dd, J = 4.3, 2.7 Hz, 1H), 5.83 - 5.72 (m, 1H), 5.67 - 5.58(m, 1H), 5.07 (t, J = 7.6 Hz, 1H), 2.98 (dt, J = 13.2, 6.6 Hz, 1H), 2.86 (dd,J = 13.3, 7.0 Hz, 1H), 2.76 - 2.69 (m, 1H), 2.64 - 2.54 (m, 2H), 2.26 (s,1H), 2.18 - 2.07 (m, 1H), 1.77 - 1.68 (m, 1H).

[0207] Example 10.1 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1, 2'-pyrrolo[2,1-b]oxazol-3-yl)oxy)isonicotinamide (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (23 mg, 0.078 mmol, I-20-trans), DMF (3 mL), 4-cyano-2-fluoropyridine (11.9 mg, 0.097 mmol), and Cs₂CO₃ (38.1 mg, 0.117 mmol) were sealed in a microwave-safe container and stirred overnight at room temperature. The reaction mixture was partitioned between pH 7 buffer and ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by rapid chromatography [SiO2, 80 g column, [3:1(v / v) / EtOAc:EtOH] / hexane mixture (0% to 70%)] to give 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile. MS (ESI) m / z [M+H] + : 398. 1 H NMR (500 MHz, CDCl3-) d) δ 8.31-8.27 (m, 1H), 7.09 (dd, J = 5.2, 1.3 Hz, 1H), 7.04-7.00 (m,1H), 6.84-6.77 (m, 2H), 6.73 (m, 1H), 5.63 (m, 1H), 5.47 (m, 1H), 5.00 (t, J= 7.4 Hz, 1H), 3.03-2.92 (m, 2H), 2.77-2.57 (m, 3H), 2.25 (ddd, J = 16.0,7.9, 4.7 Hz, 1H), 2.01 (m, 1H), 1.82-1.71 (m, 1H).

[0208] Example 10.2 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1, 2'-Pyrrolo[2,1-b]oxazolyl]-3-yl)oxy)isonicotinamide 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile (12 mg, 0.030 mmol, Example 10.1), ethanol (0.5 ml), and Ghaffar-Parkins catalyst (2.59 mg, 6.04 µmol) were sealed in a microwave-safe container and stirred overnight at 100 °C. The reaction mixture was partitioned between pH 7 buffer and ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by preparative TLC (silica gel) (expanded via a mixture of [3:1(v / v) / EtOAc:EtOH] / hexane (1:1, v / v)) to give 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide. MS (ESI) m / z [M+H] + For C 21 H 20 Calculated value of F2N3O4: 417, Measured value: 417. 1 H NMR (500 MHz, methanol-) d 4 ) δ 8.24 (d, J = 5.3 Hz, 1H), 7.34 (dd, J= 5.3, 1.4 Hz, 1H), 7.20 (s, 2H), 6.98-6.91 (m, 3H), 6.85 (m, 1H), 5.77(dd, J = 7.2, 5.0 Hz, 1H), 5.52-5.40 (m, 1H), 4.97 (t, J = 7.8 Hz, 1H), 3.07-2.98(m, 1H), 2.89-2.81 (m, 1H), 2.71 (m, 2H), 2.58 (dd, J = 13.1, 6.9 Hz, 1H), 2.27 (ddd, J = 11.8, 7.1, 2.8 Hz, 1H), 2.06-1.95 (m, 1H), 1.75 (m, 1H), 1.31(s, 1H).

[0209] Example 10.3 (1r,3R,5'S,7a'R)-3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-5'-(3,5-difluorobenzene) (3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one) 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile (10 mg, 0.025 mmol, Example 10.1), DMSO (0.5 mL), sodium azide (4.91 mg, 0.075 mmol), and aluminum sulfate (3.18 µl, 0.025 mmol) were sealed in a microwave-safe container and stirred at 140 °C for 2 days. The reaction was quenched with 0.5 mL of pH 7 buffer. The crude mixture was partitioned between water and ethyl acetate, and the combined organic extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified by reverse-phase chromatography to give (1r,3R,5'S,7a'R)-3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI) m / z [M+H] + For C 21 H 19 Calculated value of F2N6O3: 441, measured value: 441. 1 H NMR (500 MHz, CD3OD) δ 8.32 (d, J= 5.3 Hz, 1H), 7.37 (dd, J = 5.3,1.4 Hz, 1H), 7.22 (s, 1H), 6.98-6.91 (m, 3H), 6.85 (tt, J = 9.1, 2.3 Hz, 1H), 5.77 (dd, J = 7.2, 5.0 Hz, 1H), 5.46 (m, 1H), 4.97 (t, J = 7.9 Hz, 1H), 3.08-3.00(m, 1H), 2.89-2.82 (m, 1H), 2.77-2.69 (m, 1H), 2.67 (s, 1H), 2.59 (dd, J =12.8, 6.5 Hz, 1H), 2.27 (ddd, J = 11.7, 7.1, 2.7 Hz, 1H), 2.06-1.96 (m, 1H), 1.80-1.70 (m, 1H).

[0210] The compounds presented in Table 10 were prepared using a procedure similar to that described for Examples 10.1, 10.2, and 10.3, using intermediates appropriately selected from Table 4 or I-18. Unless otherwise stated, all products are in the trans configuration.

[0211] Table 10 .

[0212] Example 11.1 (1r,3R,5'S,7a'R)-3-((7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy)-5'-(3,5- (difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one In a microwave-safe vial, (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20-trans) (30 mg, 0.10 mmol), DMF (1 mL), 7-bromo-4-chloropyrrolo[2,1-F][1,2,4]triazine (28.3 mg, 0.12 mmol), and Cs₂CO₃ (49.7 mg, 0.15 mmol) were added. The vial was capped and heated at 60 °C for 3 h. The reaction solution was quenched with pH 7 buffer and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and evaporated to obtain the crude product, which was purified by reversed-phase HPLC (TFA modified) to obtain (1r,3R,5'S,7a'R)-3-((7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. MS (ESI) m / z [M+H] + For C 21 H 18 Calculated value of BrF2N4O3: 491, measured value: 491. 1 H NMR (500 MHz, CDCl3- d ) δ 8.15 (s, 1H), 6.93 (d, J = 4.6 Hz, 1H), 6.85-6.78 (m, 2H), 6.77-6.70 (m, 2H), 5.72 (m,1H), 5.67-5.63 (m, 1H), 5.01 (t, J = 7.4 Hz, 1H), 3.14-3.00 (m, 2H), 2.79 (m,2H), 2.64 (m, 1H), 2.27 (m, 1H), 2.02 (ddt, J = 13.8, 10.1, 7.0 Hz, 1H), 1.78(m, 1H).

[0213] Example 11.2 4-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1, 2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazine-7-carboxynitrile In a reaction vial, (1r,3R,5'S,7a'R)-3-((7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (4 mg, 8 µmol), Pd2(dba)3 (0.74 mg, 0.81 µmol), 1,1'-bis(diphenylphosphine)ferrocene (0.45 mg, 0.81 µmol), zinc cyanide (1.9 mg, 0.016 mmol), and DMF / H2O (99:1, v / v) (3 mL) were added. The vial was then sealed and bubbled with N2 for 30 min. The reaction mixture was placed in an oil bath at 140 °C for 3 h and then slowly cooled to room temperature. The crude product was quenched with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified by rapid chromatography (SiO2, 80 g) (eluting with a mixture of [3:1(v / v) / EtOAc:EtOH] / hexane (0 to 70%)) to give 4-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazine-7-carboxynitrile. MS (ESI) m / z [M+H] + For C 22 H 18 Calculated value of F2N5O3: 438, Measured value: 438. 1 H NMR (500 MHz, CDCl3- d ) δ 8.25 (s, 1H), 7.24 (d, J = 4.2Hz, 1H), 6.87 (d, J = 4.3 Hz, 1H), 6.80 (d, J = 6.0 Hz, 2H), 6.74 (m, 1H), 5.78-5.69 (m, 1H), 5.66 (s, 1H), 5.01 (s, 1H), 3.08 (m, 2H), 2.81 (dd, J = 12.9, 6.1Hz, 2H), 2.64 (s, 1H), 2.33-2.22 (m, 1H), 2.05 (m, 2H).

[0214] The compounds presented in Table 11 below were prepared using a procedure similar to that described for Examples 11.1 and 11.2, using intermediates appropriately selected from Table 4. Unless otherwise stated, all products are in the trans configuration.

[0215] Table 11 .

[0216] Examples 12.1 and 12.2 (1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R or S)-1-(5-fluoropyridin-2-yl)ethoxy) Tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one and (1R,3R,5'S,7a'R)-5'-(3,5-di) (Fluorophenyl)-3-((S or R)-1-(5-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutene-1,2'-pyrrolo[2,1- b]Oxazol-3'-one Towards( 1r , 3R , 5'S , 7a'R 30.0 mg (0.10 mmol) of 1-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20-trans) was added to a solution of 2-(1-bromoethyl)-5-fluoropyridine (24.9 mg, 0.12 mmol) and potassium tert-butoxide (34.2 mg, 0.305 mmol) in DMF (1 mL). The resulting mixture was capped and stirred at 80 °C for 2 h. The reaction solution was cooled, filtered, and the filtrate was concentrated and purified by reversed-phase preparative HPLC (Boston Green ODS column 150 mm x 30 mm x 5 μm; water (0.01% TFA)-ACN) to give the crude product (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-(1-(5-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one. This substance was separated by chiral SFC (ChiralPak AD (250 mm x 30 mm x 10 μm), conditions: 0.1% NH3H2O, in MeOH) to give two diastereomers as white solids, peaks 1 and 2. MS (ESI) m / z [M+H] + For C 22 H 22 Calculated value of F3N2O3: 419, Measured value: 419.

[0217] Example 12.1 (SFC Peak 1): 1H NMR (400 MHz, CD3OD): δ 8.39 (d, J=2.86 Hz, 1H), 7.54-7.67 (m, 2H), 6.75-6.97 (m, 3H), 5.63 (dd, J=5.07, 7.21 Hz, 1H), 4.89-4.94 (m, 1H), 4.56 (q, J=6.56 Hz, 1H), 4.21 (quin, J=7.36 Hz, 1H), 2.61-2.71(m, 2H), 2.38-2.54 (m, 2H), 2.14-2.27 (m, 2H), 1.94 (dddd, J=6.62, 7.99,11.37, 13.13 Hz, 1H), 1.66 (tt, J=7.58, 11.67 Hz, 1H), 1.43 (d, J=6.56 Hz, 3H).

[0218] Example 12.2 (SFC Peak 2): 1 H NMR (400 MHz, CD3OD): δ 8.39 (d, J=2.74 Hz, 1H), 7.54-7.68 (m, 2H), 6.78-6.98 (m, 3H), 5.66 (dd, J=5.01, 7.27 Hz, 1H), 4.89-4.94 (m, 1H), 4.56 (q, J=6.56 Hz, 1H), 4.21 (quin, J=7.36 Hz, 1H), 2.80-2.80(m, 1H), 2.75 (td, J=6.53, 12.70 Hz, 1H), 2.65 (dtd, J=2.62, 7.78, 13.17 Hz,1H), 2.54 (dd, J=7.81, 12.82 Hz, 1H), 2.39 (dd, J=7.27, 12.52 Hz, 1H), 2.14-2.21 (m, 2H), 1.87-1.99 (m, 1H), 1.59-1.69 (m, 1H), 1.43 (d, J=6.56 Hz, 3H).

[0219] The compounds presented in Table 12 below were prepared using a procedure similar to that described for Examples 12.1 / 12.2, with appropriately selected intermediates and reagents. SFC peak 4 in the following examples is inactive.

[0220] Table 12 .

[0221] Example 13 (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyridine] [2,1-b]oxazolium-3-ylpyridinecarboxylate To a stirred solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20-trans) (30 mg, 0.10 mmol) in DCM (1 mL), 2-pyridinecarboxylic acid (17.5 mg, 0.142 mmol), DCC (31.4 mg, 0.152 mmol), and DMAP (2.48 mg, 0.020 mmol) were added. After stirring at room temperature for 2.5 h, the reaction mixture was diluted with CH2Cl2 (25 mL) and washed successively with cold water (10 mL) and saturated NaHCO3 aqueous solution (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The oil was purified by reversed-phase preparative HPLC (water (10 mM NH4HCO3)-ACN, starting B 35, ending B 65, gradient) to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylpyridinecarboxylate. MS (ESI) m / z [M+H] + For C 21 H 19 Calculated value of F2N2O4: 401, Measured value: 401. 1 H NMR (400 MHz, CD3OD -d4) δ 8.69 (dd, J = 0.78, 4.8 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.02 (dt, J = 1.7, 7.7 Hz, 1H), 7.65 (ddd, J = 1.2, 4.8, 7.7 Hz, 1H), 7.01-6.80(m, 3H), 5.76 (dd, J = 5.0, 7.3 Hz, 1H), 5.47 (quin, J = 7.3 Hz, 1H), 4.96 (t, J=7.8 Hz, 1H), 3.07-2.95 (m, 2H), 2.77-2.68 (m, 3H), 2.29 - 2.22 (m, 1H), 2.04-1.94 (m, 1H), 1.77-1.7 (m, 1H).

[0222] Example 14 (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyridine] [2,1-b]oxazolyl]-3-ylbenzoate Benzoyl chloride (36 mg, 0.25 mmol) was added to a solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20-trans) (50 mg, 0.17 mmol) and DIEA (89 µl, 0.51 mmol) in DCM (1 mL). The resulting mixture was stirred at 20 °C for 12 h. The reaction solution was directly concentrated, and the residue was purified by reversed-phase preparative HPLC (TFA) to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylbenzoate as a white solid. MS (ESI) m / z [M+H] + For C 22 H 20 Calculated value of F2NO4: 400, Measured value: 400. 1 H NMR (400 MHz, CD3OD -d4) δ 8.07 - 8.00 (m, 2H), 7.58 - 7.65 (m, 1H), 7.52 - 7.44 (m, 2H), 6.99 - 6.90 (m, 2H), 6.85 (tt, J = 2.3, 9.1 Hz, 1H), 5.76 (dd, J = 5.0, 7.3 Hz,1H), 5.42 (quin, J = 7.3 Hz, 1H), 4.96 (t, J = 7.8 Hz, 1H), 3.04-2.96 (m, 1H), 2.91 (ddd, J= 1.6, 7.0, 13.6 Hz, 1H), 2.73 - 2.63 (m, 3H), 2.29 - 2.21 (m,1H), 2.03-1.93 (m, 1H), 1.73 (tt, J = 7.6, 11.7 Hz, 1H).

[0223] Examples 15.1, 15.2, 15.3, and 15.4 ((1S or R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S or R)-1-phenylethoxy)tetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one and ((1R or S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S or R)-1-phenylethoxy)tetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one and ((1S or R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R or S)-1-phenylethoxy)tetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one and ((1R or S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R or S)-1-phenylethoxy)tetrahydro- 3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one To a solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20) (10 mg, 0.034 mmol) in DCM (0.2 mL) and n-hexane (0.8 mL), (1-bromoethyl)benzene (12.5 mg, 0.068 mmol), silver oxide (I / III) (23.5 mg, 0.102 mmol), and 4A molecular sieve were added. The reaction mixture was washed with N2, sealed, and stirred in the dark under N2 at 60 °C for 2 h. The mixture was cooled, filtered through diatomaceous earth, and concentrated. The residue was purified by reversed-phase preparative HPLC (TFA) to give the crude product. The product mixture was resolved by chiral SFC (column: DAICL CHIRALPAK IG (250 mm x 10 mm, 10 μm), mobile phase: A: CO2, B: 0.1% NH3H2O ​​in MeOH) to give four diastereomers of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-(1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one as white solids.

[0224] Example 15.1 (Peak 1): MS (ESI) m / z [M+Na] + For C 23 H 23 Calculated value of F2NNaO3: 422, Measured value: 422. 1H NMR (400 MHz, CD3OD -d4) δ 7.38-7.23 (m, 5H), 6.94 - 6.78 (m, 3H), 5.61(dd, J = 5.0, 7.2 Hz, 1H), 4.92 (br s, 1H), 4.46 (q, J = 6.5 Hz, 1H), 4.18 - 4.09(m, 1H), 2.70 - 2.60 (m, 2H), 2.48 - 2.33 (m, 2H), 2.26 - 2.13 (m, 2H), 1.93(dddd, J = 6.6, 7.9, 11.3, 13.1 Hz, 1H), 1.65 (tt, J = 7.6, 11.7 Hz, 1H), 1.41(d, J = 6.6 Hz, 3H).

[0225] Example 15.2 (Peak 2): MS (ESI) m / z [M+Na] + For C 23 H 23 Calculated value of F2NNaO3: 422, Measured value: 422. 1 H NMR (400 MHz, CD3OD -d4) δ 7.42 - 7.19 (m, 5H), 6.99 - 6.74 (m, 3H), 5.64 (dd, J = 5.1, 7.1 Hz, 1H), 4.87 (br s, 1H), 4.45 (q, J = 6.4 Hz, 1H), 4.13(quin, J = 7.5 Hz, 1H), 2.76 - 2.58 (m, 2H), 2.51 (dd, J = 7.9, 12.9 Hz, 1H), 2.34 (dd, J = 7.6, 12.4 Hz, 1H), 2.22 - 2.12 (m, 1H), 2.08 (td, J = 6.7, 13.0 Hz,1H), 1.98 - 1.86 (m, 1H), 1.62 (tt, J = 7.5, 11.7 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H).

[0226] Example 15.3 (Peak 3): MS (ESI) m / z [M+H] + For C 23 H 24 Calculated value of F2NO3: 400, measured value: 400. 1 H NMR (400 MHz, CD3OD -d4) δ 7.19-7.39 (m, 4H), 6.76-6.95 (m, 3H), 5.68(dd, J=4.89, 7.63 Hz, 1H), 4.83-4.87 (m, 1H), 4.45 (q, J=6.44 Hz, 1H), 3.82(quin, J=7.06 Hz, 1H), 2.84 (td, J=6.11, 12.10 Hz, 1H), 2.65 (dtd, J=2.21,7.76, 13.28 Hz, 1H), 2.50 (td, J=6.24, 12.19 Hz, 1H), 2.40 (dd, J=7.33, 11.98Hz, 1H), 2.11-2.21 (m, 2H), 1.91 (dddd, J=6.56, 8.23, 11.74, 13.29 Hz, 1H), 1.58 (tt, J=7.75, 11.92 Hz, 1H), 1.41 (d, J=6.44 Hz, 3H).

[0227] Example 15.4 (Peak 4): MS (ESI) m / z [M+H] + For C 23 H 24 Calculated value of F2NO3: 400, measured value: 400. 1H NMR (400 MHz, CD3OD -d4δ 7.22-7.36 (m, 5H), 6.77-6.92 (m, 3H), 5.65(dd, J=4.89, 7.63 Hz, 1H), 4.85-4.88 (m, 1H), 4.46 (q, J=6.56 Hz, 1H), 3.83(quin, J=7.06 Hz, 1H), 2.81 (td, J=6.24, 12.19 Hz, 1H), 2.66 (dtd, J=2.21,7.77, 13.25 Hz, 1H), 2.48-2.58 (m, 1H), 2.27 (dd, J=7.33, 12.58 Hz, 2H), 2.14-2.22 (m, 1H), 1.91 (dddd, J=6.62, 8.23, 11.73, 13.25 Hz, 1H), 1.61 (tt,J=7.73, 11.88 Hz, 1H), 1.41 (d, J=6.44 Hz, 3H).

[0228] Examples 16.1 and 16.2 ((1s or r),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-phenoxytetrahydro-3'H-spiro[cyclobutane-1, 2'-pyrrolo[2,1-b]oxazol]-3'-one and ((1r or s),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-phenoxytetrahydro-3'H-spiro[cyclobutane-1, 2'-pyrrolo[2,1-b]oxazol]-3'-one In a 20 mL pressure-resistant vial, phenylboronic acid (165 mg, 1.35 mmol) was added to a solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20) (80 mg, 0.27 mmol) in DCE (4 mL). N , N -Dimethylpyridin-4-amine (6.6 mg, 0.05 mmol), pyridine (0.065 mL, 0.81 mmol), and molecular sieve (4A). The reaction mixture was stirred at 80 °C for 10 min, and then copper diacetate (49 mg, 0.27 mmol) was added. The resulting mixture was stirred at 80 °C for 12 h under an O2 balloon (1 atm). The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by reversed-phase preparative-HPLC to give two diastereomers. MS (ESI) m / z [M+H] + For C 21 H20 Calculated value of F2NO3: 371, Measured value: 371.

[0229] Example 16.1 (Peak 1 / cis): 1 H NMR (400MHz, CDCl3-d) δ = 7.25 - 7.21 (m, 2H),6.93 (br t, J = 7.3 Hz, 1H), 6.84 - 6.55 (m, 5H), 5.60 (br t, J = 5.7 Hz, 1H),5.00 - 4.85 (m, 2H), 2.91 (ddd, J = 6.9, 12.9, 19.4 Hz, 2H), 2.69 - 2.54 (m,3H), 2.26 - 2.16 (m, 1H), 2.00 - 1.91 (m, 1H), 1.23 (s, 1H).

[0230] Example 16.2 (Peak 2 / cis): 1 H NMR (400MHz, CDCl3-d) δ = 7.27 (br s, 2H),7.02 - 6.90 (m, 1H), 6.89 - 6.65 (m, 5H), 5.69 - 5.58 (m, 1H), 5.02 - 4.92(m, 1H), 4.71 - 4.58 (m, 1H), 3.22 - 3.03 (m, 2H), 2.70 - 2.56 (m, 2H), 2.50(br d, J = 6.6 Hz, 1H), 2.21 (br d, J = 3.2 Hz, 1H), 2.08 - 1.88 (m, 1H), 1.23(br s, 1H).

[0231] The compounds presented in Table 13 below were prepared using a procedure similar to that described for Examples 16.1 / 16.2, using intermediate I-26 and reagents.

[0232] Table 13 .

[0233] Examples 17.1 and 17.2 2-((((1s or r),3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane] Alkyl-1,2'-pyrrolo[2,1-b]oxazolyl-3-yl)oxy)-5-fluoroisocyanonitrile and 2-((((1r or s),3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane] Alkyl-1,2'-pyrrolo[2,1-b]oxazolyl-3-yl)oxy)-5-fluoroisocyanonitrile Step 1. (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((5-fluoro-4-iodopyridin-2-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Potassium tert-butoxide (38 mg, 0.034 mmol) and 2,5-difluoro-4-iodopyridine (61.2 mg, 0.254 mmol) were added to a solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-hydroxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-20) (50 mg, 0.17 mmol) in DMSO (2 mL). The reaction mixture was stirred at 80 °C for 12 h. The reaction solution was filtered and purified by preparative HPLC (instrument EJ; water (TFA)-MeCN) to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((5-fluoro-4-iodopyridin-2-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (15 mg) as a yellow oil. MS (ESI) m / z [M+H] + For C 20 H 17 Calculated value of F3IN2O3: 517, Measured value: 517.

[0234] Step 2. 2-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisocyanonitrile Under a nitrogen atmosphere, zinc dicyanide (6.8 mg, 0.058 mmol), zinc (0.51 mg, 7.7 µmol), 1,1'-bis(diphenylphosphine)ferrocene (4.3 mg, 7.7 µmol), and Pd2(dba)3 (3.6 mg, 3.9 µmol) were added to a solution of (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((5-fluoro-4-iodopyridin-2-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (10 mg, 0.019 mmol) in DMF (1 mL). The mixture was stirred at 100 °C for 12 h, during which time the color deepened to dark brown. The mixture was cooled, filtered, and purified by preparative-HPLC (instrument EJ; water (TFA)-MeCN) to give 2-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisocyanonitrile as a colorless oil. A purified mixture of diastereomers of 2-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisonicotinonitrile (10 mg, 0.024 mmol) was subjected to SFC (instrument SFC-25, method column DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 (μm), conditions: neutral-IPA) separation to obtain two diastereomers of 2-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisonicotinonitrile, SFC-peak 1, (100 ee%, RT = 3.81 min) and SFC-peak 2, (99 ee%, RT = 4.55 min), both white solids. MS (ESI) m / z [M+H] + For C 21 H 17 Calculated value of F3N3O3: 416, Measured value: 416.

[0235] Example 17.1 (SFC-Peak 1 / cis): 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 6.96(d, J = 3.81 Hz, 1H), 6.80 (br d, J= 6.44 Hz, 2H), 6.69-6.76 (m, 1H), 5.64 (dd, J = 5.13, 6.91 Hz, 1H), 5.06-5.15 (m, 1H), 4.99 (t, J = 7.7 Hz, 1H), 3.10-3.17(m, 2H), 2.55-2.69 (m, 2H), 2.44-2.51 (m, 1H), 2.20-2.28 (m, 1H), 1.98 (tdd, J = 6.94, 11.0, 13.5 Hz, 1H), 1.64-1.74 (m, 1H).

[0236] Example 17.2 (SFC-Peak 2 / cis): 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 3.1 Hz, 1H), 7.65 (dd, J = 3.0, 6.9 Hz, 1H), 6.77-6.83 (m, 2H), 6.72 (tt, J = 2.4, 8.7Hz, 1H), 5.65 (dd, J = 5.0, 7.0 Hz, 1H), 5.20 (t, J = 7.0 Hz, 1H), 4.99 (t, J = 7.6Hz, 1H), 3.12-3.19 (m, 2H), 2.55-2.71 (m, 3H), 2.20-2.29 (m, 1H), 1.93-2.04(m, 1H), 1.65-1.76 (m, 1H).

[0237] Example 18.1 (1S,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-ylmethoxy)tetrahydro-3'H-spiro[cyclobutane] [Alkyl-1,2'-pyrrolo[2,1-b]oxazol]-3'-one] (1S,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (61.0 mg, 0.152 mmol) (I-38-cis), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1 mol%), and 3-bromopyridine (16 mg, 0.101 mmol) were added to a 4 mL glass vial equipped with a magnetic stir bar and dissolved in DMF. Morpholine (13.23 µl, 0.152 mmol) was added. In a second vial, nickel(II) ethylene glycol dimethyl ether complex (2.225 mg, 10.13 µmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (2.72 mg, 10.13 µmol) were added and dissolved in DMF. The mixture was sonicated for 30 seconds and heated with a hot air gun until a clear green solution was obtained. The two mixtures were combined, and the resulting reaction mixture with a total molar concentration of 0.1 M was irradiated with a blue LED (445 nm, 220 mW) for 2 h. The mixture was analyzed, and the product was identified. The crude mixture was directly purified.

[0238] The crude product was purified by reversed-phase chromatography (eluting with acetonitrile / water + 0.05% TFA) to give (1S,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-ylmethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 18.1). MS (ESI) m / z [M+H] + : 353; 1H NMR (499 MHz, CDCl3) δ 8.65(d, J = 1.3 Hz, 1H), 8.59 (s, 1H), 8.55 (d, J = 3.8 Hz, 1H), 8.53 - 8.52 (m,1H), 8.51 (d, J = 2.5 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.8,4.9 Hz, 1H), 5.67 (dd, J = 7.0, 5.0 Hz, 1H), 5.12 - 5.07 (m, 1H), 4.48 (s,2H), 4.07 (p, J = 6.9 Hz, 1H), 2.91 (dt, J = 11.8, 6.1 Hz, 1H), 2.85 (dt, J =12.2, 6.1 Hz, 1H), 2.64 - 2.56 (m, 1H), 2.43 (dd, J = 11.9, 7.2 Hz, 1H), 2.34(dd, J = 11.9, 7.1 Hz, 3H), 1.76 - 1.65 (m, 1H).

[0239] The compounds presented in Table 14 below were prepared using a procedure similar to that described for Example 18.1, using appropriate intermediates selected from Table 6, commercially available or known aromatic electrophiles. Unless otherwise known, all products are plotted in cis or trans configuration.

[0240] Table 14 .

[0241] Example 19.1 (5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrazinyloxy] [2,1-b]oxazol]-3'-one Under N2 conditions, AdCyBrettPhos-Pd-G3 (40 mg, 0.042 mmol) was added to a mixture of 3-bromopyridine (27.2 mg, 0.172 mmol), 3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-29-cis) (30 mg, 0.115 mmol), and cesium carbonate (112 mg, 0.344 mmol) in THF (40 mL). The reaction mixture was stirred at 100 °C for 16 h. LC-MS showed the formation of the desired target product. The crude product was purified by reversed-phase chromatography (eluting with water (10 mM NH4HCO3)-MeCN) to give (5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 19.1).

[0242] MS (ESI) m / z [M+H] + : 339; 1H NMR (400 MHz, methanol-d4) δ 8.70 (d, J=1.19 Hz,1H), 8.59-8.63 (m, 1H), 8.55 (d, J=2.50 Hz, 1H), 8.17-8.20 (m, 1H), 8.11-8.15(m, 1H), 7.36 (t, J=2.09 Hz, 2H), 5.79 (dd, J=4.95, 7.33 Hz, 1H), 5.13 (t, J=7.69 Hz, 1H), 4.67 (quin, J=6.77 Hz, 1H), 3.06-3.20 (m, 2H), 2.65-2.76 (m,1H), 2.57-2.64 (m, 1H), 2.43-2.53 (m, 1H), 2.19-2.38 (m, 2H), 1.65-1.84 (m,1H).

[0243] Example 19.2 (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-(3-(1-methyl-1H-pyrazole-5-yl)phenoxy) Tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Under N2, 5-(3-bromophenyl)-1-methyl-1H-pyrazole (32.4 mg, 0.137 mmol), Cs2CO3 (111 mg, 0.342 mmol), and RockPhos-Pd-G3 (9.55 mg, 0.011 mmol) were added to a solution of (1R,3R,5'S,7a'R)-3-hydroxy-5'-(1-methyl-1H-pyrazole-3-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-34-cis) (30 mg, 0.114 mmol) in toluene (2 mL). The resulting mixture was stirred under N2 at 100 °C for 12 h. LC-MS showed that SM had been consumed and the desired MS peak was observed. The solid was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by reversed-phase chromatography (eluting with water (10 mM NH4·HCO3)-MeCN) to give (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-(3-(1-methyl-1H-pyrazol-5-yl)phenoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 19.2). MS (ESI) m / z [M+H] + : 420.2; 1H NMR (400MHz, methanol-d4) δ 7.50 (dd, J=2.09, 10.43 Hz, 2H), 7.37-7.42 (m, 1H), 7.04-7.08(m, 1H), 6.93-6.96 (m, 2H), 6.36 (d, J=2.03 Hz, 1H), 6.23 (d, J=2.27 Hz, 1H), 5.69 (dd, J=5.07, 6.85 Hz, 1H), 5.00 (t, J=7.33 Hz, 1H), 4.62-4.66 (m, 1H), 3.86 (d, J=5.36 Hz, 6H), 3.04-3.12 (m, 2H), 2.51-2.59 (m, 2H), 2.39-2.46 (m,1H), 2.15-2.26 (m, 2H), 1.61-1.73 (m, 1H).

[0244] The compounds presented in Table 15 below were prepared using a procedure similar to that described for Examples 19.1 and 19.2, with appropriate intermediates selected from Table 5 and suitable solvents, bases, and commercially available or known aromatic electrophiles. Unless otherwise known, all products are plotted in cis or trans configuration.

[0245] Table 15 .

[0246] Example 20.1 (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-(3-(1-methyl-1H-pyrazole-5-yl)phenoxy) Tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one In a glove box, cesium carbonate (455 mg, 1.396 mmol), 2-bromo-3-methylpyridine (144 mg, 0.837 mmol), and CataCXium A-Pd-G3 (68.1 mg, 0.084 mmol) were added to a solution of (5'S,7a'R)-5'-(pyrazin-2-yl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborheoctan-2-yl)methoxy) in dioxane (3 ml) and H2O (0.600 ml). The mixture was stirred at 80 °C for 12 h under N2. LCMS showed the desired product mass. The crude product was purified by reversed-phase chromatography (eluting with water (10 mM - NH4·HCO3)-MeCN) to give (5'S,7a'R)-3-((3-methylpyridin-2-yl)methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 20.1) MS (ESI). m / z [M+H] + 367; 1 H NMR (400 MHz, methanol-d4) δ ppm8.66 (d, J=1.31 Hz, 1H), 8.56-8.62 (m, 1H), 8.53 (d, J=2.50 Hz, 1H), 8.28-8.34 (m, 1H), 7.66 (d, J=7.63 Hz, 1H), 7.30 (dd, J=7.63, 4.89 Hz, 1H), 5.69-5.75 (m, 1H), 5.07 (t, J=7.63 Hz, 1H), 4.59 (s, 2H), 4.01 (quin, J=6.94 Hz,1H), 2.75-2.86 (m, 2H), 2.61-2.72, (m, 1H), 2.43 (s, 3H), 2.33-2.40 (m, 1H), 2.16-2.30 (m, 3H), 1.62-1.76 (m, 1H).

[0247] The compounds presented in Table 16 below were prepared using a procedure similar to that described for Example 20.1, using appropriate intermediates, commercially available or known aromatic electrophiles selected from Table 6. Unless otherwise known, all products are plotted in cis or trans configuration.

[0248] Table 16 .

[0249] Example 20.10 cis-(5'S,7a'R)-3-{[4-(1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one Cesium carbonate (345 g, 1.06 mmol), 2-(4-bromophenyl)-1,3,4-oxadiazole (52.4 g, 233 mmol), and CataCXium A-Pd-G3 (46.2 g, 63.5 mmol) were added to a solution of (5'S,7a'R)-5'-(pyrazin-2-yl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)methoxy) in dioxane (1.1 L) and H2O (75 mL). The mixture was stirred at 80 °C for 12 h under N2. The desired product mass was observed by LCMS. The mixture was added to 1000 mL of EDTA and stirred at 25 °C for 1 h. It was then extracted with 1500 mL of DCM (500 mL * 3) and washed with brine (500 mL * 1). The residue was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the final product. The crude residue was first purified by column chromatography (SiO2, ethyl acetate / methanol = 1 / 0 to 10 / 1) followed by preparative HPLC (column: Welch Xtimate C18 250 * 100 mm # 10 μm; mobile phase: [H2O (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; gradient: 15%–45% B, over 20.0 min) to provide cis-(5'S,7a'R)-3-{[4-(1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one (13.3 g, 31.7 mmol). MS (ESI) m / z [M+H] + 420.2, 1 H NMR: (400MHz, DMSO-d6) δ= 9.34 (s, 1H),8.71 - 8.67 (m, 1H), 8.64 - 8.61 (m, 1H), 8.60 - 8.57 (m, 1H), 8.01 (d, 1H, J =8.4 Hz), 7.56 (d, 1H, J = 8.4 Hz), 5.74 - 5.64 (m, 1H), 5.07 - 4.97 (m, 1H), 4.51 (s, 2H), 3.98 - 3.85 (m, 1H), 2.85 - 2.73 (m, 2H), 2.63 - 2.53 (m, 1H), 2.34 - 2.26 (m, 1H), 2.25 - 2.16 (m, 2H), 2.13 - 2.01 (m, 1H), 1.66 - 1.54 (m, 1H).

[0250] Examples 21.1 and 21.2 (1s,3S,5'S,7'S,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclic] Butane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (1s,3S,5'S,7'R,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclic] Butane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one Step 1. ( R 2-Methyl-N-(pyrazin-2-ylmethylene)propane-2-sulfinamide Add ( ) to a solution of pyrazine-2-carboxaldehyde (10 g, 93 mmol) in DCM (300 ml) at 25 °C. S 2-Methylpropane-2-sulfinamide (13.4 g, 111 mmol) and Cs₂CO₃ (90 g, 278 mmol) were added and the mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a brown oil. The oil was purified by column chromatography (SiO₂, 330 g ISCO column, eluted with 10-70% EtOAc / hexane) to give ( R )-2-methyl- N -(pyrazin-2-ylmethylene)propane-2-sulfinamide. MS (ESI) m / z [M+H] + : 212.

[0251] Step 2. Preparation of (R)-N-((S)-4,4-dimethoxy-3-oxo-1-(pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide Hexamethyldisilazane lithium salt (35.5 mL, 35.5 mmol) was added to a solution of acetone aldehyde dimethyl acetal (3.91 g, 33.1 mmol) in THF (50 mL) and stirred at -60 °C for 1 h. (R)-2-methyl-N-(pyrazin-2-ylmethylene)propane-2-sulfinamide (5 g, 23.66 mmol) in THF (50 mL) was added, and the mixture was stirred at -60 °C for 4 h. LCMS showed the presence of the desired compound. The mixture was poured into an aqueous solution of NaHCO3 (50 mL) and water (20 mL) and extracted with EA (100 mL x 3). The mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to obtain the crude product. The crude product was purified by reversed-phase MPLC, and the mixture was resolved by chiral SFC (conditions: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm)), mobile phase: A: CO2, B: CO2-EtOH (0.1% NH3H2O), gradient: 0.15% B, flow rate: 60 mL / min) to give (R)-N-((S)-4,4-dimethoxy-3-oxo-1-(pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide (950 mg, 2.88 mmol, yield 67.9%) as a yellow oil. MS (ESI) m / z [M+H] + : 330.

[0252] Step 3. Preparation of (R)-N-(3-hydroxy-4,4-dimethoxy-1-(pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide Sodium borohydride (218 mg, 5.77 mmol) was added to a solution of (R)-N-(4,4-dimethoxy-3-oxo-1-(pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide (950 mg, 2.88 mmol) in MeOH (9 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 0.5 h. LCMS showed the presence of the desired compound. Water (10 mL) was added to the mixture and extracted with DCM:MeOH (10:1 = 10 mL * 3). The mixture was concentrated to give (R)-N-(3-hydroxy-4,4-dimethoxy-1-(pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide (950 mg, 2.87 mmol, 99% yield) as a yellow oil. MS (ESI) m / z [M+H] + : 332.

[0253] Step 4. Preparation of (4S)-4-amino-1,1-dimethoxy-4-(pyrazin-2-yl)but-2-ol Acetyl chloride (0.245 mL, 3.44 mmol) was added to a solution of (R)-N-((1S)-3-hydroxy-4,4-dimethoxy-1-(pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide (950 mg, 2.87 mmol) in MeOH (10 mL) at 0 °C under N2. The reaction mixture was stirred at 20 °C for 12 h. LC-MS showed the presence of the desired compound. TEA was added to the reaction mixture to pH ~8. The mixture was directly concentrated to give (4S)-4-amino-1,1-dimethoxy-4-(pyrazin-2-yl)but-2-ol (651 mg, 2.87 mmol, 100% yield) as a yellow oil, which was used directly for the next step without further purification. MS (ESI) m / z [M+H] + : 227.

[0254] Step 5. Preparation of 3-(benzyloxy)-1-hydroxy-N-((1S)-3-hydroxy-4,4-dimethoxy-1-(pyrazin-2-yl)butyl)cyclobutane-1-carboxamide To a solution of 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxylic acid (500 mg, 2.250 mmol) in DMF (3 mL), (4S)-4-amino-1,1-dimethoxy-4-(pyrazin-2-yl)but-2-ol (614 mg, 2.70 mmol), TEA (0.627 mL, 4.50 mmol), HOBT (456 mg, 3.37 mmol), and EDC (647 mg, 3.37 mmol) were added, and the resulting mixture was stirred at 25 °C for 1 h. LCMS showed the presence of the desired compound. The mixture was filtered and concentrated. The mixture was extracted with water (30 mL) and EA (10 mL x 3). The mixture was concentrated to give 3-(benzyloxy)-1-hydroxy-N-((1S)-3-hydroxy-4,4-dimethoxy-1-(pyrazin-2-yl)butyl)cyclobutane-1-carboxamide (971 mg, 2.250 mmol, 100% yield) as a yellow oil. MS (ESI) m / z [M+H] + : 432. Step 6. Preparation of (1s,3S,5'S,7'S,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 21.1) and (1s,3S,5'S,7'R,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 21.2). MsOH (0.376 mL, 5.79 mmol) was added to a solution of 3-(benzyloxy)-1-hydroxy-N-((1S)-3-hydroxy-4,4-dimethoxy-1-(pyrazin-2-yl)butyl)cyclobutane-1-carboxamide (500 mg, 1.159 mmol) in DCM (3 mL), and the resulting mixture was stirred at 25 °C for 12 h. LC-MS showed that the reaction was complete and the desired product was found. The mixture was adjusted to pH 9 with TEA (3 mL). The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (preparative HPLC conditions: preparative HPLC was performed on a Phenomenex Gemini-NX 150*30mm*5μm instrument, using mobile phase AB: water (10 mM HCOONH4)-ACN, gradient: 20-50% B, 0-11 min; 100% B, 11-13.5 min; 10% B, 13.5-15.5 min. Flow rate: 25 mL / min). The residue was then purified by chiral SFC (conditions: SFC-21 (column: REGIS (R,R)WHELK-O1 (250mm*25mm, 10μm)), mobile phase: A: CO2, B: CO2-i-PrOH (0.1% NH3H2O), gradient: 0.45% B, flow rate: 80 mL / min). The mixture was split at a rate of mL / min to obtain (1s,3S,5'S,7'S,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 21.1) and (1s,3S,5'S,7'R,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 21.2).

[0255] (1s,3S,5'S,7'S,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 21.1) MS (ESI) m / z [M+H] + 368; 1 H NMR (400 MHz, methanol-d4) δ 8.68 (d, J = 1.4 Hz, 1H), 8.62 (dd, J = 1.8, 2.50 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 4.4Hz, 4H), 7.25-7.31 (m, 1H), 5.40 (d, J = 5.6 Hz, 1H), 5.08 (t, J = 8.8 Hz, 1H), 4.45 (s, 2H), 3.91-4.07 (m, 2H), 2.74-2.88 (m, 3H), 2.34-2.47 (m, 1H), 2.18-2.34 (m, 2H) (1s,3S,5'S,7'R,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 21.2) MS (ESI) m / z [M+H] + 368; 1 H NMR (400 MHz, methanol-d4) δ 8.68 (d, J = 1.6 Hz, 1H), 8.60 (dd, J = 1.2, 2.40 Hz, 1H), 8.53 (d, J =2.8 Hz, 1H), 7.34 (d, J = 4.4 Hz,4H), 7.22-7.31 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 5.04 (t, J = 8.8 Hz, 1H), 4.46(s, 2H), 4.11 (t, J = 2.80 Hz, 1H), 3.99 (quin, J = 6.4 Hz, 1H), 2.72-2.86 (m,2H), 2.55 (dd, J= 8.4, 13.6 Hz, 1H), 2.29-2.43 (m, 3H) Example 22.1 (1S,3S,5'S,7a'R)-3-((2-chlorobenzyl)oxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-] 1,2'-pyrrolo[2,1-b]oxazol]-3'-one NaH (6.12 mg, 0.230 mmol) was added to a dried 4 mL sample vial in a glove box. A solution of (1S,3S,5'S,7a'R)-3-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (40 mg, 0.153 mmol) in 2-Me-THF was added, and the mixture was stirred at ambient temperature for 10 min. Then, a solution of 1-(bromomethyl)-2-chlorobenzene (62.9 mg, 0.306 mmol) in 2-Me-THF was added. The final concentration reached 0.1 M. The vial was sealed, removed from the glove box, and heated to 50 °C for 14 h. As determined by LC-MS, near-complete conversion was achieved. The reaction solution was cooled, slowly quenched with saturated NH4Cl aqueous solution (1 mL), diluted with DCM (3 mL), and passed through a phase separator. The crude product was concentrated under vacuum and purified by reversed-phase preparative HPLC to give (1s,3S,5'S,7a'R)-3-((2-chlorobenzyl)oxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one (Example 22.1).

[0256] MS (ESI) m / z [M+H] +: 386. 1H NMR (499 MHz, DMSO-d6) δ 8.71 (d, J = 1.4Hz, 1H), 8.64 (dd, J = 2.4, 1.5 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.53 -7.49 (m, 1H), 7.48 - 7.45 (m, 1H), 7.38 - 7.34 (m, 2H), 5.70 (dd, J = 7.3,5.0 Hz, 1H), 5.03 (t, J = 7.8 Hz, 1H), 4.50 (s, 2H), 3.94 (p, J = 6.9 Hz,1H), 2.80 (ddd, J = 12.4, 6.1, 1.3 Hz, 2H), 2.59 (dtd, J = 13.1, 8.1, 2.5 Hz,1H), 2.33 - 2.28 (m, 1H), 2.21 (ddt, J = 11.5, 7.0, 3.4 Hz, 2H), 2.08 (ddt, J= 13.1, 11.1, 7.1 Hz, 1H), 1.61 (tt, J = 11.3, 8.1 Hz, 1H).

[0257] The compounds presented in Table 17 below were prepared using a procedure similar to that described for Example 22.1, using appropriate intermediates selected from Table 5, commercially available or known benzyl electrophiles. Unless otherwise known, all products are plotted in cis or trans configuration.

[0258] Table 17 .

[0259] Example 23.1 (5'S,7a'R)-3-(cyclobutylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrazinyl] [2,1-b]oxazol]-3'-one To a dried 4-mL sample vial, add cyclobutylmethanol (16.61 mg, 0.193 mmol) and triisopropylsilane (79 µl, 0.386 mmol). Under an inert atmosphere, add a solution of (5'S,7a'R)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3,3'-dione (50 mg, 0.193 mmol) in dried acetonitrile (964 µl, 0.193 mmol). Cool the resulting solution to -10 °C and treat with trimethylsilyl trifluoromethanesulfonate (69.8 µl, 0.386 mmol). The final concentration should reach 0.2 M. Age the reaction mixture at the above temperature for 18 h. Complete conversion is achieved as determined by LCMS; the desired product is formed. Quench the reaction mixture with an aqueous sodium bicarbonate solution (1 mL). The resulting suspension was transferred to a phase separator with dichloromethane (4 mL). The organic phase was concentrated and purified by an ISCO® 4 g SepaFlash® silica gel rapid column (eluent: 20%–30% isocratic EtOAc:EtOH = 3:1 / hexane; 20 CV). The isomers were further separated by a chiral SFC (column Lux-2 [250 mm × 21 mm × 5 µm]; 30% MeOH [0.1% NH4OH] / CO2; flow rate: 70 mL / min) to give peak 1 (Example 23.1) and peak 2 (Example 23.2) of (5'S,7a'R)-3-(cyclobutylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0260] Peak 1 (Example 23.1): MS (ESI) m / z [M+H] +Calculated value for C18H23N3O3: 330, Measured value: 330; 1H NMR (499 MHz, CDCl3) δ 8.67 (s, 1H), 8.53 (s, 2H), 5.66 (dd, J = 6.9, 5.0 Hz, 1H), 5.13 - 5.06 (m, 1H), 3.93 (p, J = 6.9 Hz, 1H), 3.34 (d, J = 6.9Hz, 2H), 2.88 (dt, J = 11.7, 6.0 Hz, 1H), 2.83 (dt, J = 12.1, 6.2 Hz, 1H), 2.60 (dt, J = 11.6, 8.2 Hz, 1H), 2.53 (dt, J = 15.0, 7.6 Hz, 1H), 2.36 (dd, J= 11.8, 7.3 Hz, 1H), 2.28 (ddd, J = 10.9, 8.5, 5.6 Hz, 3H), 2.09 - 2.01 (m,2H), 1.94 - 1.82 (m, 2H), 1.75 - 1.66 (m, 3H).

[0261] Peak 2 (Example 23.2): MS (ESI) m / z [M+H] + Calculated value for C18H23N3O3: 330, Measured value: 330; 1H NMR (499 MHz, CDCl3) δ 8.66 (s, 1H), 8.52 (s, 2H), 5.65 - 5.61 (m, 1H), 5.14 - 5.08 (m, 1H), 4.22 (p, J = 7.4 Hz, 1H), 3.36 - 3.30 (m, 2H), 2.72 (dd, J = 12.7, 7.8 Hz, 1H), 2.65 (dt, J = 12.8, 6.6 Hz, 1H), 2.61 - 2.50 (m, 2H), 2.44 - 2.34 (m, 2H), 2.32 - 2.23 (m, 2H), 2.09 - 2.01 (m, 2H), 1.95 -1.82 (m, 2H), 1.78 - 1.68 (m, 3H).

[0262] The compounds presented in Table 18 below were prepared using a procedure similar to that described for Example 23.1, using appropriately selected commercially available or known alcohols. Unless otherwise known, all products are plotted in cis or trans configuration.

[0263] Table 18 .

[0264] Measurement RIPK1-ADP-Glo ​​enzymatic assay The enzymatic activity of RIPK1 was measured using an assay derived from the ADP-Glo ​​kit (TMPromega), which provides a luminescent ADP detection system. Specifically, ADP produced by the RIPK1 kinase was detected homogeneously as a luminescent signal. In this context, the inhibitory effect of small molecules (EC50) was assessed by measuring the effectiveness of the compound in inhibiting RIPK1's conversion of ATP to ADP.

[0265] In this assay, the potency (EC50) of each compound was determined using a ten-point (1:3 serial dilution; highest compound concentration 100,000 nM) titration curve using the steps outlined below. 30 nL of the compound (1% DMSO in a final assay volume of 3 µL) was dispensed into each well of a white ProxiPlus 384-well plate, followed by 2 µL of 1x assay buffer (25 mM Hepes 7.3, 20 mM MgCl2, 50 mM NaCl, 1 mM DTT, 0.005% Tween 20, and 0.02% BSA) containing 37.5 nM GST-RIPK1 (recombinant GST-RIPK1 kinase domain (residues 1-327) produced from baculovirus-transfected Sf21 cells). The plate was incubated in a humidified chamber at ambient temperature for 30 minutes with the compound. Subsequently, each reaction was initiated by adding 1 µL of 1x assay buffer containing 900 µM ATP and 3 µM dephosphorylated MBP substrate. The final reaction solution in each well consisted of 3 µL of 25 nM GST-RIPK1, 300 µM ATP, and 3 µM dephosphorylated MBP. The kinase reaction was allowed to proceed for 150 minutes before adding the ADP-Glo ​​reagent according to Promega's outline kit protocol. Dose-response curves were generated by plotting percentage of effect (% product conversion; Y-axis) against Log10 compound concentration (X-axis). EC50 values ​​were calculated using a nonlinear regression, four-parameter sigmoidal dose-response model.

[0266] Valence Table 。

Claims

1. Compounds of formula (I) Or its pharmaceutically acceptable salt, wherein: for or ; R 1 -(R) 7 )mR 8 ; R 2 It is H or (C1-C6) alkyl; R 3 It is H or halogen; R 4 It is H or halogen; R 5 It is H or halogen; R 6 It is H or halogen; R 7 It is (C1-C6)alkyl or (C1-C6)carbonyl; R 8 for a) An aryl group, optionally substituted with up to three of the following groups: halogen, O(C1-C6)alkyl, O(C3-C6)cycloalkyl, (C3-C8)cycloalkyl optionally substituted with a nitrile group, O-(C1-C6)alkyl-O-CH3, C(O)NH2, (C1-C6)alkyl optionally substituted with up to three halogens, S(O)2-CH3, (C1-C6)nitrile, ((C1-C6)alkyl) having up to three heteroatoms selected from N, O and S and further optionally substituted with (C1-C6)alkyl. p -(C5-C6)heteroaryl, wherein the (C1-C6)alkyl group is optionally substituted with up to 3 halogens; b) A heteroaryl group having up to five heteroatoms selected from N, O, and S, and optionally substituted by up to three of the following groups: halogen, O(C1-C6)alkyl, O(C1-C6)alkyl-F, S(C1-C6)alkyl, C(O)NH2, (C1-C6)alkyl optionally substituted by up to three halogens, (C1-C6)nitrile, (C3-C8)cycloalkyl optionally substituted by a nitrile group, ((C1-C6)alkyl) p -Aryl, having up to 3 heteroatoms selected from N, O and S ((C1-C6)alkyl) p -(C5-C6) heterocyclic group, having up to 3 heteroatoms selected from N, O and S, optionally substituted with (C1-C6)alkyl groups ((C1-C6)alkyl). p -(C5-C6)heteroaryl, optionally substituted with (C5-C6)heterocyclic ((C1-C6)alkyl) p -(C5-C6)cycloalkyl, wherein the (C5-C6) heterocyclic group has up to 3 heteroatoms selected from N, O, and S and is further optionally substituted with (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with up to 3 halogens; O-(C5-C6) heterocyclic group having up to 3 heteroatoms selected from N, O, and S; (C5-C6) heteroaryl group having up to 3 heteroatoms selected from N, O, and S and further optionally substituted with (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with up to 3 halogens; or c) Cycloalkyl; B is either CH or N; D is either C or N, provided that if D is N, then R 3 It does not exist; E is either C or N, provided that if E is N, then R 6 It does not exist; G is either CH or N; J is either CH or N; m is 0 or 1; n is 0 or 1; and p is 0 or 1.

2. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is .

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein B is CH and D and E are C.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein both D and E are N.

5. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein E is N.

6. The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 6 All are F.

7. The compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein R 5 It is F.

8. The compound according to any one of claims 2 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 For H.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 7 It is an (C1-C6) alkyl group and m is 1.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein m is 0.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 8 It is an aryl group that can be replaced by up to 3 halogens.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 8 It is an aryl group substituted with a (C1-C6) nitrile group.

13. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S.

14. The compound according to any one of claims 1 to 9 and 12, or a pharmaceutically acceptable salt thereof, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, and wherein said heteroaryl group is substituted with up to 3 halogens.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 12 to 13, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, wherein the heteroaryl group is substituted with a (C1-C6) nitrile group.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 12 to 14, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, wherein the heteroaryl group is substituted with (C1-C6) alkyl groups.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 12 to 15, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, wherein the heteroaryl group is substituted by a (C5-C6) heteroaryl group having up to 3 heteroatoms selected from N, O and S.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 12 to 16, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, wherein the heteroaryl group is substituted with a (C5-C6) heteroaryl group having up to 3 heteroatoms selected from N, O and S, which is further substituted with a (C1-C6) alkyl group.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and 12 to 16, wherein R 8 It is a heteroaryl group having up to 5 heteroatoms selected from N, O and S, wherein the heteroaryl group is substituted with a (C5-C6) heteroaryl group having up to 3 heteroatoms selected from N, O and S, which is further substituted with CF2.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein n is 0.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein n is 1.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is selected from: ((1r),4R,5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1s),4R,5'S,7a'R)-4-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-(benzyloxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1r),4R,5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1s),4R,5'S,7a'R)-4-(benzyloxy)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3R,5'S,7a'R)-3-(benzyloxy)-5'-(5-fluoropyridin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1r),3R,5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1s),3R,5'S,7a'R)-3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; cis-6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; trans-6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3-methyl-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxamide; cis-6-((((1r),3R,5'(S),7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; trans-6-((((1s),3R,5'(S),7a'R)-5'-(1-methyl-1H-pyrazole-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; cis-6-((((1r),3R,5'(R),7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile; trans-6-((((1s),3R,5'(R),7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxylon; (1r,3R,5'S,7a'R)-3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-(benzyloxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3S,5'S,7a'R)-3-(2,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-Fluoro-4-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)benzylnitrile; 5-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-2-carboxynitrile; 4-Fluoro-3-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-5'-phenyl-3-{[2-(trifluoromethyl)pyridin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-[(5-methoxypyridin-3-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(3-fluoropyridin-4-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-{[5-(trifluoromethyl)pyridin-3-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-{[(5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-(3-fluorophenoxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(2-chloropyridin-4-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,2-benzothiazol-4-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(4-fluoro-3-methylphenoxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,2-benzothiazol-5-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-[3-(trifluoromethyl)phenoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[3-(1,3,4-oxadiazol-2-yl)phenoxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(4-fluoro-3-methoxyphenoxy)-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,2-benzoxazol-7-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(imidazo[1,2-c]pyrimidin-5-yl)oxy]-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-[(pyrrolo[1,2-b]pyridazin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-(pyrrolo[1,2-b]pyridazine-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-3-[(pyrrolo[1,2-d][1,2,4]triazine-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 6-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; 6-(((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; (5'S,7a'R)-3-((6-chloropyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-{[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(2-methyl[1,3]thiazo[5,4-d]pyrimidin-7-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-{[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-fluoropyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-{[6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl]oxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 6-(((1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; (1s,3S,5'S,7a'R)-3-((6-chloropyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-2-carboxynitrile; 5-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-3-carboxynitrile; 6-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrazine-2-carboxynitrile; 6-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; 4-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-2-carboxynitrile; 2-{[(1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; 2-{[(1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-4-carboxynitrile; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(2-methylpyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(thieno[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(furano[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(6-methylfurano[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(6-methylthiopheno[2,3-d]pyrimidin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-[(imidazo[1,2-c]pyrimidin-5-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1s,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((5-fluoropyridin-2-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-[(2-chloropyridin-3-yl)oxy]-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(5-fluoropyridin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; cis-(5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(3-fluoropyridin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; trans-(5'S,7a'R)-5'-(3,5-difluorophenyl)-3-[(3-fluoropyridin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; cis-6-{[(5'S,7a'R)-5'-(2,3-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; trans-6-{[(5'S,7a'R)-5'-(2,3-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-4-carboxynitrile; 6-(((5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile; 6-{[(5'S,7a'R)-5'-(2-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidine-4-carboxynitrile; 6-(((5'S,7a'R)-5'-(3-cyano-5-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; (1s,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 6-{[(5'S,7a'R)-5'-(5-fluoropyridin-2-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyrimidin-4-carboxynitrile; (1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3-[(5-fluoropyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-{[(1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}pyridine-3-carboxynitrile; 6-(((5'R,7a'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidin-4-carboxynitrile; (1s,3R,5'R,7a'S)-5'-(pyrazin-2-yl)-3-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-phenyl-4-[(pyrazin-2-yl)oxy]tetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-((6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((6-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)oxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-3-((6-(4-(difluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrimidine-4-carboxynitrile; 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile; 2-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide; (1r,3R,5'S,7a'R)-3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinonitrile; 2-(((1r,3R,5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide; 2-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)isonicotinamide; (1r,3R,5'S,7a'R)-3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)oxy)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-3-((7-bromopyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 4-(((1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazine-7-carboxynitrile; 4-(((1r,3R,5'S,7a'R)-5'-(4-fluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)pyrrolo[2,1-f][1,2,4]triazine-7-carboxynitrile; cis-(1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-(5-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; trans-(1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-(5-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1R,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-(3-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1S,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-(3-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1R,3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((s)-1-(3-fluoropyridin-2-yl)ethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylpyridinecarboxylate; (1r,3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-ylbenzoate; ((1S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((S)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-((R)-1-phenylethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1S),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-phenoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; ((1R),3R,5'S,7a'R)-5'-(3,5-difluorophenyl)-3-phenoxytetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1R),(5'S,7a'R)-5'-(5-fluoropyridin-3-yl)-4-phenoxytetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (1S),(5'S,7a'R)-5'-(5-fluoropyridin-3-yl)-4-phenoxytetrahydro-3'H-spiro[cyclohexane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 2-((((1S),3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisocyanonitrile; 2-((((1R),3S,5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)-5-fluoroisocyanonitrile; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[(imidazo[1,2-a]pyrazin-8-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[([1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[(pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(4-fluorophenyl)-3-[(pyridin-4-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(3-fluoropyridin-2-yl)-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1r,3R,5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyrrolo[2,1-f][1,2,4]triazine-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyrazin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1S,3S,5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-ylmethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[([1,2,4]triazolo[4,3-a]pyrimidin-6-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1-cyclopropyl-1H-pyrazole-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(pyrazolo[1,5-a]pyrimidin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1-methyl-1H-pyrazole-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1-phenyl-1H-pyrazole-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-ethoxypyrimidin-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-({3-[2-(4H-1,2,4-triazol-4-yl)ethyl]phenyl}methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[5-(difluoromethyl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-benzyl-1,3,4-thiadiazol-2-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({6-[(but-2-yl)oxy]pyridin-2-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)quinoline-8-carboxynitrile; (5'S)-3-{[5-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[3-(methylthio)[1,2,4]triazolo[4,3-a]pyridin-6-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[4-(methanesulfonyl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-b]pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-d]pyrimidin-6-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(4-fluoroisoquinoline-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1s,3S,5'S,7a'R)-3-[(1,3-benzothiazo-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[2-(morpholin-4-yl)pyrimidin-5-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({4-[(1H-imidazol-1-yl)methyl]phenyl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-({3-[(1H-1,2,3-triazol-1-yl)methyl]phenyl}methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-(2-fluoroethoxy)pyridin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 1-[5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]cyclobutane-1-carboxynitrile; 1-[3-chloro-4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]cyclopropane-1-carboxynitrile; (5'S)-3-{[4-(1,2-oxazol-3-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(pyrazolo[1,5-a]pyrimidin-7-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-methoxy-1,7-naphthyl-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-chloro-2-(1,3-oxazol-5-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-methoxyimidazo[1,2-a]pyridin-7-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[6-(morpholin-4-yl)pyridin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(isoquinolin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [2-Methoxy-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[4-(1H-imidazol-1-yl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-(cyclobutoxy)-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-3-[(2-methoxy-8-methylquinoline-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(5,6,7,8-tetrahydroquinolin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[3,2-b]pyridin-2-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[6-(2-fluoroethoxy)pyridazin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridine-4-carboxylonitrile; (5'S)-3-[(imidazo[1,2-a]pyrimidin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-[4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]propionitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)-1,3-benzothiazo-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-chloro-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]acetonitrile; (5'S)-3-{[4-(2-methoxyethoxy)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-Fluoro-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[1-(pyridin-4-yl)-1H-pyrazol-4-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(1H-pyrazol-1-yl)phenyl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)furan-3-carboxynitrile; (5'S)-3-{[4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({6-[(oxan-4-yl)oxy]pyridin-3-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[4-(1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1,2-benzoxazol-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(pyrazolo[1,5-a]pyrimidin-7-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(1,3-benzothiazo-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[5-(difluoromethyl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-benzyl-1,3,4-thiadiazol-2-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)quinoline-8-carboxynitrile; (5'S,7a'R)-3-({6-[(but-2-yl)oxy]pyridin-2-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[4-(methanesulfonyl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-b]pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(6-methoxypyridin-3-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-cyclopropyl-1,3-thiazolyl-4-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(4-fluoroisoquinoline-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({4-[(1H-imidazol-1-yl)methyl]phenyl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 5-Methoxy-6-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridine-2-carboxynitrile; (5'S)-5'-(pyrazin-2-yl)-3-({3-[(1H-1,2,3-triazol-1-yl)methyl]phenyl}methoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-(2-fluoroethoxy)pyridin-3-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 1-[5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]cyclobutane-1-carboxynitrile; 1-[3-chloro-4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]cyclopropane-1-carboxynitrile; (5'S)-3-{[4-(1,2-oxazol-3-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2-methoxy-1,7-naphthyl-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-{[5-chloro-2-(1,3-oxazol-5-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(5-methoxyimidazo[1,2-a]pyridin-7-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(imidazo[1,2-a]pyridin-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(isoquinolin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [2-Methoxy-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]acetonitrile; (5'S)-3-{[4-(1H-imidazol-1-yl)pyridin-2-yl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-(cyclobutoxy)-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-3-[(2-methoxy-8-methylquinoline-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(5,6,7,8-tetrahydroquinolin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-[(thieno[3,2-b]pyridin-2-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-[(2,3-dihydro-1-benzofuran-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridine-4-carboxylonitrile; (5'S)-3-[(imidazo[1,2-a]pyrimidin-6-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-[4-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]propionitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)-1,3-benzothiazo-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; [3-chloro-5-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)pyridin-2-yl]acetonitrile; (5'S)-3-{[4-(2-methoxyethoxy)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-Fluoro-2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S)-5'-(pyrazin-2-yl)-3-{[1-(pyridin-4-yl)-1H-pyrazol-4-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(1H-pyrazol-1-yl)phenyl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 2-({[(5'S)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)furan-3-carboxynitrile; (5'S)-3-{[4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-3-({6-[(oxan-4-yl)oxy]pyridin-3-yl}methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S)-5'-(pyrazin-2-yl)-3-(thieno[2,3-d]pyrimidin-6-ylmethoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S)-3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-(pyridin-3-yloxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-(3-(1-methyl-1H-pyrazol-5-yl)phenoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; 3-Fluoro-5-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-(3,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-{[(1s,3S,5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3'-oxotetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(6-methylpyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-(1-methyl-1H-pyrazol-3-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-[3-(1-methyl-1H-pyrazol-5-yl)phenoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(pyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazole-3-yl)-3-[(6-methylpyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-3-yl)-3-(3-(1-methyl-1H-pyrazol-5-yl)phenoxy)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(pyridin-2-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(2-methyl-2H-indazol-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[([1,2,4]triazolo[4,3-a]pyrimidin-5-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(2-methylpyridin-3-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(1,3-benzothiazo-5-yl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 1-[4-({[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)phenyl]cyclopropane-1-carboxynitrile; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-(1-methyl-1H-pyrazol-3-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; cis-(1s,3S,5'S,7'S,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; trans-(1s,3S,5'S,7'R,7a'R)-3-(benzyloxy)-7'-hydroxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 5'-(5-Fluoropyridin-2-yl)-3-[(pyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(pyrazin-2-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(2,5-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-((((5' S ,7a' R )-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3-yl)oxy)methyl)benzylnitrile; (5' S ,7a' R )-3-(benzo[ d Isoxazol-6-ylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazol]-3'-one; cis-(5'S,7a'R)-3-[3-(1-methyl-1H-pyrazol-5-yl)phenoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; trans-(5'S,7a'R)-3-[3-(1-methyl-1H-pyrazole-5-yl)phenoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 3-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; (5'S,7a'R)-3-phenoxy-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(5-chloropyridin-3-yl)oxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(thieno[2,3-b]pyridin-3-yl)methoxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[6-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl]oxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-5'-(pyrazin-2-yl)-3-[(pyridin-3-yl)oxy]tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(3,4-difluorophenoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (1S,3S,5'S,7a'R)-3-((2-chlorobenzyl)oxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; 3-Fluoro-5-{[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}benzylnitrile; 4-((((5' S ,7a' R )-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazolyl]-3-yl)oxy)methyl)benzylnitrile; (5' S ,7a' R )-3-((5-chloro-3-methylpyridin-2-yl)methoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; (5' S ,7a' R )-5'-(pyrazin-2-yl)-3-(thiophen-2-ylmethoxy)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-] b [Oxazol]-3'-one; (5'S,7a'R)-3-[(3-fluorophenyl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-[(3-chlorophenyl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; 4-({[(5'S,7a'R)-3'-oxo-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3-yl]oxy}methyl)benzylnitrile; (5'S,7a'R)-3-[(3-fluorophenyl)methoxy]-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-{[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy}-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b][1,3]oxazol]-3'-one; (5'S,7a'R)-3-(cyclobutylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; Cis-(5') S ,7a' R )-3-(cyclopentylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one; and trans-(5') S ,7a' R )-3-(cyclopentylmethoxy)-5'-(pyrazin-2-yl)tetrahydro-3' H -spiro[cyclobutane-1,2'-pyrrolo[2,1-b]oxazol]-3'-one.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is selected from: 。 24. A method for treating RIPK1-dependent inflammation and cell death occurring in hereditary and sporadic diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis, and acute tissue damage caused by stroke, traumatic brain injury, or encephalitis, the method comprising administering to a patient in need a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22.

25. A method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a patient in need a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

26. Use of the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof for the treatment of amyotrophic lateral sclerosis in patients with such need.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22 and a pharmaceutically acceptable carrier.

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