Spirotricyclic RIPK1 inhibitors and methods of use thereof

Abstract

Described herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein A, R 1 , R 2 , R 3 , W, X, Y, Z, m, n and p are as defined herein. Compounds of formula I act as RIPK1 inhibitors and may be useful in preventing, treating or acting as therapeutic agents for RIPK1-related diseases. [Formula 1] TIFF2024541944000353.tif62165

Description

[Technical field]

[0001] The present invention is directed to RIPK1 inhibitors. In particular, the RIPK1 inhibitors described herein can be useful in preventing or treating RIPK1-related diseases, or can be useful as therapeutic agents for RIPK1-related diseases. [Background technology]

[0002] 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 wide range of neurodegenerative, autoimmune and inflammatory diseases in humans. This is supported by extensive studies that have shown that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways.

[0003] For example, inhibition of RIPK1 has been shown to be useful as a treatment for acute kidney injury (AKI), a devastating clinical condition caused by multiple insults such as ischemia-reperfusion, nephrotoxic drugs, and sepsis. RIPK1-mediated necroptosis has been shown to play an important role in AKI, and RIPK1 inhibitors may be promising clinical candidates for the treatment of AKI. Wang JN, et al., RIPK1 Inhibitor Cpd-71 Attenuates Renal Dysfunction in Cisplatin-Treated Mice via Attenuating Necroptosis, Inflammation and Oxidative Stress, Clin Sci (Lond.) 2019 Jul 25;133(14):1609-1627.

[0004] Furthermore, human genetic evidence has linked RIPK1 dysregulation to the pathogenesis of amyotrophic lateral sclerosis (ALS), Alzheimer's disease and multiple sclerosis, as well as other inflammatory and neurodegenerative diseases. Degterev A., et al., Targeting RIPK1 for the treatment of human diseases, Proc. Natl. Acad. Sci. USA, May 14, 2019, 116 (20), 9714-9722; Ito Y, et al., RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS, Science, 2016, 353:603~8; Caccamo A, et al., Necroptosis activation in Alzheimer's disease, Nat Neurosci, 2017, 20:1236~46; Ofengeim D, et al., Activation of necroptosis in multiple sclerosis, Cell Rep., 2015, 10:1836~49.

[0005] Furthermore, necroptosis has also been shown to be a delayed component of ischemic neuronal injury. Therefore, inhibition of RIPK1 may also play a promising role in the treatment of stroke. 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. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Wang JN, et al., RIPK1 Inhibitor Cpd-71 Attenuates Renal Dysfunction in Cisplatin-Treated Mice via Attenuating Necroptosis, Inflammation and Oxidative Stress, Clin Sci (Lond.) 2019 Jul 25;133(14):1609-1627 [Non-Patent Document 2] Degterev A., et al., Targeting RIPK1 for the treatment of human diseases, Proc. Natl. Acad. Sci. USA, May 14, 2019, 116 (20), 9714-9722 [Non-Patent Document 3] Ito Y, et al., RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS, Science, 2016, 353:603-8 [Non-Patent Document 4] Caccamo A, et al., Necroptosis activation in Alzheimer's disease, Nat Neurosci, 2017, 20:1236-46 [Non-Patent Document 5] Ofengeim D, et al., Activation of necroptosis in multiple sclerosis, Cell Rep., 2015, 10:1836-49 [Non-Patent Document 6] 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 Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is a need for highly selective RIPK1 inhibitors that are able to cross the blood-brain barrier, thereby offering the potential to target neuroinflammation and cell death that lead to various neurological conditions such as Alzheimer's disease, ALS, and multiple sclerosis, as well as acute neurological disorders such as stroke and traumatic brain injury. [Means for solving the problem]

[0008] Described herein is a compound of formula I: [ka] [In the formula, A, W, X, Y, Z, R 1 , R 2 , R 3 , n, m and p are described below. and pharma- ceutically acceptable salts thereof.

[0009] The compounds described herein are RIPK1 inhibitors and may be useful for preventing, treating, or ameliorating neurodegenerative, autoimmune, and inflammatory diseases, as well as other RIPK1-associated diseases.

[0010] Also described herein are methods of treating neurodegenerative, autoimmune and inflammatory diseases, comprising administering to a patient in need of such treatment a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0011] Also described herein is the use of the compounds described herein, or pharma- ceutically acceptable salts thereof, for treating neurodegenerative diseases, autoimmune diseases, and inflammatory diseases in a patient in need of such treatment.

[0012] Also described herein are pharmaceutical compositions that include a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0013] Also described herein are pharmaceutical compositions that include a compound described herein and a pharma- ceutically acceptable carrier.

[0014] Also described herein are methods of treating neurodegenerative, autoimmune and inflammatory diseases, comprising administering to a patient in need of such treatment a compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0015] Also described herein is the use of a compound described herein, or a pharma- ceutically acceptable salt thereof, in combination with at least one additional agent, for treating neurodegenerative, autoimmune, and inflammatory diseases in a patient in need of such treatment.

[0016] Also described herein are pharmaceutical compositions that include a compound described herein, or a pharma- ceutically acceptable salt thereof, at least one additional therapeutic agent, and a pharma- ceutically acceptable carrier.

[0017] Also described herein are pharmaceutical compositions that include a compound described herein, at least one additional therapeutic agent, and a pharma- ceutically acceptable carrier. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Described herein is a compound of formula I: [ka] [During the ceremony, A is aryl, heteroaryl, heterocycloalkyl, or C3-C6 cycloalkyl; R 1 each occurrence is independently selected from the group consisting of: -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), and C1-C6 alkoxy; W is CH, N, O or S; X is C(R 4 )2, N, O, or S, where if X is N, then there is a dashed line connecting X; 4 )2, O or S, there is no dashed line connecting X; where X is C(R 4 )2, then Y is N, O or S, and when X is N, O or S, then Y is CH2; Y is CH, N, O, or S, where when Y is N, there is a dashed line connecting Y; where when Y is CH, O, or S, there is no dashed line connecting Y; and when Y is N, O, or S, X is C(R 4 )2; R 2 is hydrogen, -OH, C1-C6 alkylOH, CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl) or C1-C6 alkoxy, or when X or Y is N, R 2 does not exist; R 3 is hydrogen, -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl) or C1-C6 alkoxy; R 4 each occurrence is independently selected from the group consisting of hydrogen, -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), and C1-C6 alkoxy; Z is -CN, aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SOaryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl, -SO2heterocycloalkyl, -COOC1-C6 alkyl or -COOC3-C6 cycloalkyl, wherein the aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10Cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl or -SO2heterocycloalkyl are unsubstituted or substituted with halogen, -CN, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOC1-C6 alkyl. substituted with 1 to 3 substituents independently selected from the group consisting of aryl, -SC1-C6 alkyl, oxo, C3-C6 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, and C1-C6 alkoxy are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, and heterocycloalkyl; m is 0, 1, 2 or 3; n is 1 or 2; and p is 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0019] Described herein are compounds where A is aryl, heteroaryl, heterocycloalkyl, or C3-C6 cycloalkyl. In certain embodiments, A is aryl, heteroaryl, or C3-C6 cycloalkyl. In certain embodiments, A is aryl. In certain embodiments where A is aryl, the aryl is phenyl.

[0020] In certain embodiments, A is heteroaryl. Suitable heteroaryls include, but are not limited to, pyridyl (pyridinyl), oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, benothiophenyl, isothiazolyl, and isoquinolyl. In certain embodiments where A is heteroaryl, the heteroaryl is pyridinyl, pyrazinyl, benothiophenyl, isothiazolyl, or thienyl.

[0021] In certain embodiments where A is heteroaryl, the heteroaryl is [ka] It is.

[0022] In certain embodiments, A is heterocycloalkyl. Suitable heterocycloalkyls include, but are not limited to, azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and dihydrocyclopentapyridinyl. In certain embodiments, A is heterocycloalkyl, A is: [ka] It is.

[0023] In certain embodiments, A is C3-C6 cycloalkyl. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, A is C3-C6 cycloalkyl, the C3-C6 cycloalkyl is cyclohexyl or cyclopentyl.

[0024] In certain embodiments, A is [ka] It is.

[0025] Described herein is R 1 is a compound independently selected from the group consisting of -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), and C1-C6 alkoxy. 1 is -CN, C1-C6 alkyl, halogen or C1-C6 alkoxy.

[0026] In certain embodiments, R 1 is -OH. In certain embodiments, R 1 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol.

[0027] In certain embodiments, R 1 is -CN. In certain embodiments, R 1 is C1-C6 alkylCN. Suitable examples include, but are not limited to: [ka] etc.

[0028] In certain embodiments, R 1is a C1-C6 alkyl. Suitable alkyls include, but are not limited to, 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, and 1-ethyl-1-methylpropyl. In certain embodiments, R 1 is methyl.

[0029] In certain embodiments, R 1 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0030] In certain embodiments, R 1 is a halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R 1 is fluorine.

[0031] In certain embodiments, R 1 is -NH2.

[0032] In certain embodiments, R 1 is -N(C1-C6 alkyl). In certain embodiments, R 1 is -N(CH3)2.

[0033] In certain embodiments, R 1 is -NH(C1-C6 alkyl). In certain embodiments, R 1 is -NH(CH3).

[0034] In certain embodiments, R 1 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 1 is methoxy.

[0035] Described herein are compounds where m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 1 or 2.

[0036] In certain embodiments of the compounds described herein, A is phenyl, m is 0, 1, or 2, and R 1 is fluorine, methoxy, methyl or -CN.

[0037] In certain embodiments of the compounds described herein, A is pyridinyl, m is 0, 1, or 2, and R 1 is fluorine, methyl or -CN.

[0038] Described herein are compounds where W is CH2, N, O, or S. In certain embodiments, W is CH2. In certain embodiments, W is N. In certain embodiments, W is O. In certain embodiments, W is S. In certain embodiments where W is N, X is CH2 and Y is CH2. In certain embodiments where W is O, X is CH2 and Y is CH2. In certain embodiments where W is S, X is CH2 and Y is CH2.

[0039] Described herein is a compound in which X is C(R 4 )2, N, O, or S, where when X is N, there is a dashed line connecting X; where X is C(R4 )2, O or S, there is no dashed line connecting X; where X is C(R 4 )2, Y is N, O, or S, and where X is N, O, or S, Y is CH2. In certain embodiments, X is CH2, N, O, or S, where when X is N, there is a dashed line connecting X. In certain embodiments, X is C(R 4 )2, O or S, there is no dashed line connecting X. In certain embodiments, X is C(R 4 )2, where R 4 are described in detail below. In certain embodiments, X is CH2. In certain embodiments, X is N. In certain embodiments, X is O. In certain embodiments, X is S. In certain embodiments, X is C(R 4 )2, then Y is N, O, or S. In certain embodiments, when X is N and Y is CH2, there is a dashed line connecting X. In other embodiments, when X is N, O, or S, then Y is CH2.

[0040] Described herein are compounds where Y is CH, N, O, or S, where when Y is N, there is a dashed line connecting Y; where when Y is CH, O, or S, there is no dashed line connecting Y; and where when Y is N, O, or S, X is C(R 4 )2. In certain embodiments, when Y is N, there is a dashed line connecting to Y. In certain embodiments, when Y is CH2, O, or S, there is no dashed line connecting to Y. In certain embodiments, Y is CH2. In certain embodiments, Y is N. In certain embodiments, Y is O. In certain embodiments, Y is S. In another embodiment, when Y is N, O, or S, X is C(R 4 )2. In another embodiment, when Y is N, O or S, X is CH2.

[0041] In certain embodiments, Y is O and X is CH2. In certain embodiments, Y is S and X is CH2. In certain embodiments, Y is CH2 and X is O. In certain embodiments, Y is N, X is CH2 and there is a dashed line connecting Y.

[0042] In certain embodiments, when Y is CH, X is C(R 4 )2. In certain embodiments, when X is N, O or S, then W cannot be N, O or S.

[0043] Described herein is R 2 is hydrogen, -OH, C1-C6 alkylOH, CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl) or C1-C6 alkoxy, or when X or Y is N, R 2 is a non-existent compound.

[0044] In certain embodiments, R 2 is hydrogen.

[0045] In certain embodiments, R 2 is -OH. In certain embodiments, R 2 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol.

[0046] In certain embodiments, R 2 is -CN. In certain embodiments, R 2 is C1-C6 alkylCN. Suitable C1-C6 alkylCN include, but are not limited to: [ka] etc.

[0047] In certain embodiments, R 2 is a C1-C6 alkyl. Suitable alkyls include, but are not limited to, 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, and 1-ethyl-1-methylpropyl. In certain embodiments, R 2 is methyl.

[0048] In certain embodiments, R 2 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0049] In certain embodiments, R 2 is a halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R 2 is fluorine.

[0050] In certain embodiments, R 2 is -NH2.

[0051] In certain embodiments, R 2 is -N(C1-C6 alkyl). In certain embodiments, R 2 is -N(CH3)2.

[0052] In certain embodiments, R 2 is -NH(C1-C6 alkyl). In certain embodiments, R2 is -NH(CH3).

[0053] In certain embodiments, R 2 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 2 is methoxy.

[0054] In certain embodiments where a dashed line is present, R 2 In certain embodiments, when X or Y is N, R 2 For example, in formula Ic below, when Y is N, X is CH2, and the dashed line is present, R 2 Similarly, in certain embodiments, when X is N, Y is CH2, and the dashed line is present, R 2 does not exist.

[0055] In certain embodiments, described herein are compounds of formula Ia, formula Ib, formula Ic, and formula Id: [ka] It is a compound represented by the formula:

[0056] Described herein are compounds where n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0057] Described herein are compounds where p is 1 or 2. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0058] In certain embodiments, the compound of formula II [ka] As shown in, n and p are both 1.

[0059] In certain embodiments, the compound of formula III [ka] As shown in, n and p are both 2.

[0060] Described herein is R 3 is hydrogen, -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, N(C1-C6 alkyl)2, -NH(C1-C6 alkyl) or C1-C6 alkoxy.

[0061] In certain embodiments, R 3 is hydrogen.

[0062] In certain embodiments, R 3 is -OH. In certain embodiments, R 3 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol.

[0063] In certain embodiments, R 3 is -CN. In certain embodiments, R 3 is C1-C6 alkylCN. Suitable C1-C6 alkylCN include, but are not limited to: [ka] etc.

[0064] In certain embodiments, R 3is a C1-C6 alkyl. Suitable alkyls include, but are not limited to, 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, and 1-ethyl-1-methylpropyl. In certain embodiments, R 3 is methyl.

[0065] In certain embodiments, R 3 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0066] In certain embodiments, R 3 is a halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R 3 is fluorine.

[0067] In certain embodiments, R 3 is -NH2.

[0068] In certain embodiments, R 3 is -N(C1-C6 alkyl). In certain embodiments, R 3 is -N(CH3)2.

[0069] In certain embodiments, R 3 is -NH(C1-C6 alkyl). In certain embodiments, R 3 is -NH(CH3).

[0070] In certain embodiments, R 3 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 3 is methoxy.

[0071] Described herein is R 4 is a compound in which each occurrence is independently selected from the group consisting of hydrogen, -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), and C1-C6 alkoxy. 4 Each occurrence of is hydrogen or -OH.

[0072] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is -OH. In certain embodiments, R 4 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol.

[0073] In certain embodiments, R 4 is -CN. In certain embodiments, R 4 is C1-C6 alkylCN. Suitable C1-C6 alkylCN include, but are not limited to: [ka] etc.

[0074] In certain embodiments, R 4is a C1-C6 alkyl. Suitable alkyls include, but are not limited to, 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, and 1-ethyl-1-methylpropyl. In certain embodiments, R 4 is methyl.

[0075] In certain embodiments, R 4 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0076] In certain embodiments, R 4 is a halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R 1 is fluorine.

[0077] In certain embodiments, R 4 is -NH2.

[0078] In certain embodiments, R 4 is -N(C1-C6 alkyl). In certain embodiments, R 4 is -N(CH3)2.

[0079] In certain embodiments, R 4 is -NH(C1-C6 alkyl). In certain embodiments, R 4 is -NH(CH3).

[0080] In certain embodiments, R 4 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 4 is methoxy.

[0081] Described herein are groups in which Z is -CN, aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 Cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl, -SO2heterocycloalkyl, -COOC1-C6 alkyl or -COOC3-C6 cycloalkyl, wherein the aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10Cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl or -SO2heterocycloalkyl are unsubstituted or substituted with halogen, -CN, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOC1-C6 alkyl, -SC 1-C6 alkyl, oxo, C3-C6 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, and wherein the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, and C1-C6 alkoxy are unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, and heterocycloalkyl.

[0082] In certain embodiments, Z is -CN, aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 It is cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2 heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl, -SO2 heterocycloalkyl, -COOC1-C6 alkyl or -COOC3-C6 cycloalkyl.

[0083] In certain embodiments, Z is -CN.

[0084] In certain embodiments, Z is aryl. In certain embodiments, Z is phenyl.

[0085] In certain embodiments, Z is C1-C6 alkylaryl. In certain embodiments, Z is CH2 phenyl.

[0086] In certain embodiments, Z is -COaryl. In certain embodiments, Z is -COphenyl.

[0087] In certain embodiments, Z is -CONHaryl. In certain embodiments, Z is -CONHphenyl.

[0088] In certain embodiments, Z is -SO2aryl. In certain embodiments, Z is -SO2phenyl.

[0089] In certain embodiments, Z is C-C 10 Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0090] In certain embodiments, Z is C1-C6 alkylC3-C 10 Suitable cycloalkyls include, but are not limited to, C1-C6 alkylcyclopropyl, C1-C6 alkylcyclobutyl, C1-C6 alkylcyclopentyl, and C1-C6 alkylcyclohexyl.

[0091] In certain embodiments, Z is -COC3-C 10 Suitable cycloalkyls include, but are not limited to, -COcyclopropyl, -COcyclobutyl, -COcyclopentyl and -COcyclohexyl. 10 In certain embodiments that are cycloalkyl, the -COC3-C 10Cycloalkyl is -COcyclopropyl, -COcyclobutyl, -COcyclohexane, -COcyclopentane or [ka] It is.

[0092] In certain embodiments, Z is -CONHC3-C 10 Suitable cycloalkyls include, but are not limited to, -CONHcyclopropyl, -CONHcyclobutyl, -CONHcyclopentyl, and -CONHcyclohexyl.

[0093] In certain embodiments, Z is -SO2C3-C 10 Suitable cycloalkyls include, but are not limited to, -SO2cyclopropyl, -SO2cyclobutyl, -SO2cyclopentyl, and -SO2cyclohexyl.

[0094] In certain embodiments, Z is heteroaryl. In certain embodiments where Z is heteroaryl, the heteroaryl is [ka] It is.

[0095] In certain embodiments, Z is heteroaryl. In certain embodiments where Z is heteroaryl, the heteroaryl is [ka] TIFF2024541944000017.tif232156TIFF2024541944000018.tif80127.

[0096] In certain embodiments, Z is heteroaryl, wherein the heteroaryl is: [ka] It is.

[0097] In certain embodiments, Z is C1-C6 alkylheteroaryl. In certain embodiments where Z is C1-C6 alkylheteroaryl, the C1-C6 alkylheteroaryl is [ka] It is.

[0098] In certain embodiments, Z is -COheteroaryl. In certain embodiments where Z is -COheteroaryl, the -COheteroaryl is [ka] TIFF2024541944000022.tif225144TIFF2024541944000023.tif234150TIFF2024541944000024.tif172154.

[0099] In certain embodiments, Z is -CONHheteroaryl. Suitable -CONHheteroaryls include all of the heteroaryls discussed above linked to a -CONH group.

[0100] In certain embodiments, Z is -SO2heteroaryl. Suitable -SO2heteroaryls include all of the heteroaryls discussed above bonded to a SO2 group. In certain embodiments, Z is heterocycloalkyl. Suitable heterocycloalkyls include, but are not limited to, azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and dihydrocyclopentapyridinyl.

[0101] In certain embodiments, Z is C1-C6 alkylheterocycloalkyl. Suitable C1-C6 alkylheterocycloalkyls include all of the heterocycloalkyls discussed above attached to an alkyl group.

[0102] In certain embodiments, Z is -COheterocycloalkyl. Suitable -COheterocycloalkyls include all of the heterocycloalkyls discussed above attached to a CO group.

[0103] In certain embodiments, Z is -CONHheterocycloalkyl. Suitable -CONHheterocycloalkyls include all of the heterocycloalkyls discussed above linked to a CONH group.

[0104] In certain embodiments, Z is -SO2heterocycloalkyl. Suitable -SO2heterocycloalkyls include all of the heterocycloalkyls discussed above linked to a SO2 group.

[0105] In certain embodiments, Z is -COOC1-C6 alkyl. In certain embodiments, Z is [ka] It is.

[0106] In certain embodiments, Z is -COOC3-C6 cycloalkyl. In certain embodiments, -COOCyclobutyl.

[0107] Described herein are compounds in which Z is unsubstituted or substituted. In certain embodiments, Z is unsubstituted. In certain embodiments, Z is substituted. In certain embodiments, Z is substituted with 1-3 substituents. In certain embodiments, Z is substituted with 1 substituent. In certain embodiments, Z is substituted with 2 substituents. In certain embodiments, Z is substituted with 3 substituents. In certain embodiments, Z is substituted with 1-3 substituents selected from the group consisting of halogen, -CN, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOC1-C6 alkyl, -SC1-C6 alkyl, oxo, C3-C6 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, and C1-C6 alkoxy are unsubstituted or substituted with 1-2 substituents selected from the group consisting of halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, or heterocycloalkyl.

[0108] Z is aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 In certain embodiments of cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl, or -SO2heterocycloalkyl, the aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 Cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl or -SO2heterocycloalkyl are unsubstituted or substituted with halogen, -CN, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOC1-C and each of the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, and C1-C6 alkoxy is unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, or heterocycloalkyl.

[0109] In certain embodiments, Z is substituted with a halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, Z is substituted with fluorine or chlorine.

[0110] In certain embodiments, Z is substituted with -CN.

[0111] In certain embodiments, Z is substituted with C1-C6 alkylCN. Suitable C1-C6 alkylCN groups include, but are not limited to, [ka] etc.

[0112] In certain embodiments, Z is substituted with C1-C6 alkyl. Suitable alkyls include, but are not limited to, 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, and 1-ethyl-1-methylpropyl. In certain embodiments, Z is substituted with methyl.

[0113] In certain embodiments, Z is substituted with C1-C6 alkynyl.

[0114] In certain embodiments, Z is substituted with C1-C6 haloalkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0115] In certain embodiments, Z is substituted with C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0116] In certain embodiments, Z is substituted with C1-C6 haloalkoxy. Suitable alkoxy groups include, but are not limited to, trifluoromethoxy and difluoroethoxy.

[0117] In certain embodiments, Z is substituted with -COOC1-C6 alkyl.

[0118] In certain embodiments, Z is substituted with -SC1-C6 alkyl. Suitable -SC1-C6 alkyls include, but are not limited to, -SCH3.

[0119] In certain embodiments, Z is substituted with oxo.

[0120] In certain embodiments, Z is substituted with C3-C6 cycloalkyl. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0121] In certain embodiments, Z is substituted with aryl. Suitable aryls include phenyl.

[0122] In certain embodiments, Z is substituted with heteroaryl. Suitable heteroaryls include, but are not limited to, pyridyl (pyridinyl), oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, benothiophenyl, isothiazolyl, and isoquinolyl. In certain embodiments where A is heteroaryl, the heteroaryl is pyridinyl, pyrazinyl, benothiophenyl, isothiazolyl, or thienyl.

[0123] In certain embodiments, Z is substituted with heterocycloalkyl. Suitable heterocycloalkyls include, but are not limited to, azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and dihydrocyclopentapyridinyl.

[0124] In certain embodiments, when Z is a substituted heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, or C1-C6 alkoxy, the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, or C1-C6 alkoxy is unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, or heterocycloalkyl.

[0125] In certain embodiments where Z is aryl, the aryl is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of halogen, -CN, -OH, C1-C6 alkyl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkynyl, heteroaryl, or C1-C6 haloalkoxy, where the heterocycloalkyl, C1-C6 alkynyl, or C3-C6 cycloalkyl is unsubstituted or substituted with an oxo group, -CN, or -OH.

[0126] In certain embodiments where Z is phenyl, the phenyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of -CN, chlorine, fluorine or methyl.

[0127] In certain embodiments where Z is -COaryl, the aryl is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of halogen, CN, -OH, C1-C6 alkyl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkynyl, heteroaryl, or C1-C6 haloalkoxy, where the heterocycloalkyl, C1-C6 alkynyl, or C3-C6 cycloalkyl is unsubstituted or substituted with an oxo group, -CN, or -OH.

[0128] In certain embodiments where Z is -COphenyl, the -COphenyl is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of fluorine, chlorine, iodine, -CN, ethynyl, hydroxymethylbutynyl, -OH, triazole, morpholine, oxopyrrolidinyl, difluoromethoxy, oxadiazolyl, ethyl, cyclopropyl, and methyl.

[0129] In certain embodiments where Z is heteroaryl, the heteroaryl is unsubstituted or substituted with one to four substituents selected from the group consisting of -CN, -OH, phenyl, halogen, C1-C6 alkylOH, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COC1-C6 alkyl, -COOC1-C6 alkyl, -SC1-C6 alkyl, oxo, C3-C6 cycloalkyl, heterocycloalkyl, -CONH(C1-C6 alkyl), -CONH2, -CON(C1-C6 alkyl)2, or heteroaryl, where the phenyl, C1-C6 alkoxy, or heteroaryl is unsubstituted or substituted with halogen, C1-C6 haloalkyl, heterocycloalkyl, or C1-C6 alkyl.

[0130] In certain embodiments where Z is heteroaryl, the heteroaryl is unsubstituted or substituted with one to four substituents selected from the group consisting of fluorine, bromine, -CN, methyl, methoxy, ethoxy, difluoromethyl, phenyl, methylimidazolyl, -SCH2, chlorine, trifluoromethyl, cyclopropyl, cyclobutyl, propoxy, difluoromethoxy, ethyl, difluoromethylpyrazole, methoxyoxetane, difluoroethoxy, and triazolyl.

[0131] In certain embodiments where Z is -COheteroaryl, the -COheteroaryl is unsubstituted or substituted with one to four substituents selected from the group consisting of -CN, -OH, phenyl, halogen, C1-C6 alkylOH, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COC1-C6 alkyl, -COOC1-C6 alkyl, -SC1-C6 alkyl, oxo, C3-C6 cycloalkyl, heterocycloalkyl, -CONH(C1-C6 alkyl), -CONH2, -CON(C1-C6 alkyl)2, or heteroaryl, where the phenyl, C1-C6 alkoxy, or heteroaryl is unsubstituted or substituted with halogen, C1-C6 haloalkyl, heterocycloalkyl, or C1-C6 alkyl.

[0132] In certain embodiments where Z-COheteroaryl is, the -COheteroaryl is unsubstituted or substituted with one to four substituents selected from the group consisting of fluorine, bromine, -CN, methyl, methoxy, difluoromethyl, phenyl, methylimidazolyl, -SCH2, chlorine, trifluoromethyl, cyclopropyl, propoxy, ethoxy, difluoromethoxy, ethyl, CH2CN, pyridinyl, pyrimidinyl, propyl, pyrrole, and triazolyl.

[0133] In certain embodiments where Z is -SO2aryl, the -SO2aryl is unsubstituted or substituted with halogen, -CN, or C1-C6 alkyl.

[0134] In certain embodiments where Z is -SO2phenyl, the -SO2phenyl is unsubstituted or substituted with fluorine, -CN, or methyl.

[0135] In certain embodiments, Z is unsubstituted or substituted with one to four substituents selected from the group consisting of -CN, -OH, phenyl, halogen, C1-C6 alkylOH, C1-C6 alkylCN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COC1-C6 alkyl, C1-C6 alkynyl, -COOC1-C6 alkyl, -SC1-C6 alkyl, oxo, C3-C6 cycloalkyl, heterocycloalkyl, -CONH(C1-C6 alkyl), -CONH2, -CON(C1-C6 alkyl)2, or heteroaryl, wherein the phenyl, heterocycloalkyl, C1-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or heteroaryl is unsubstituted or substituted with an oxo group, -CN or -OH, halogen, C1-C6 haloalkyl, heterocycloalkyl, or C1-C6 alkyl.

[0136] Also described herein is a compound of formula IV: [ka] [During the ceremony, A is aryl, heteroaryl, heterocycloalkyl, or C3-C6 cycloalkyl; R 1 each occurrence is independently selected from the group consisting of: -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), and C1-C6 alkoxy; Z is -CN, aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SOaryl, C3-C 10Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl, -SO2heterocycloalkyl, -COOC1-C6 alkyl or -COOC3-C6 cycloalkyl, wherein the aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10Cycloalkyl, heteroaryl, -C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl or -SO2heterocycloalkyl is unsubstituted or is selected from the group consisting of -CN, -OH, halogen, C1-C6 alkylCN, C1-C6 alkylOH, C1-C6 alkyl, C1-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOC1-C6 alkyl, -COC1-C6 alkyl, -SC 1-C6 alkyl, oxo, C3-C6 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -CONH(C1-C6 alkyl), -CONH2, -CON(C1-C6 alkyl)2, where the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, C1-C6 alkoxy is unsubstituted or substituted with 1-2 substituents independently selected from the group consisting of halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, or heterocycloalkyl; and m is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt thereof.

[0137] Also described herein is a compound of formula V: [ka] [During the ceremony, R 1 each occurrence is independently selected from the group consisting of -OH, C1-C6 alkylOH, -CN, C1-C6 alkylCN, C1-C6 alkyl, haloC1-C6 alkyl, halogen, and C1-C6 alkoxy; and Z is -CN, aryl, C1-C6 alkylaryl, -COaryl, CONHaryl, -SOaryl, C3-C 10Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10 cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl, -SO2heterocycloalkyl, -COOC1-C6 alkyl or -COOC3-C6 cycloalkyl, wherein the aryl, C1-C6 alkylaryl, -COaryl, -CONHaryl, -SO2aryl, C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, -COC3-C 10 Cycloalkyl, -CONHC3-C 10 Cycloalkyl, -SO2C3-C 10Cycloalkyl, heteroaryl, C1-C6 alkylheteroaryl, -COheteroaryl, -CONHheteroaryl, -SO2heteroaryl, heterocycloalkyl, C1-C6 alkylheterocycloalkyl, -COheterocycloalkyl, -CONHheterocycloalkyl or -SO2heterocycloalkyl are unsubstituted or are selected from the group consisting of -CN, -OH, halogen, C1-C6 alkylCN, C1-C6 alkylOH, C1-C6 alkyl, C1-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOC1-C6 alkyl, -COC1-C6 alkyl, -S and substituted with 1 to 4 substituents independently selected from the group consisting of C1-C6 alkyl, oxo, C3-C6 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -CONH(C1-C6 alkyl), -CONH2, -CON(C1-C6 alkyl)2, wherein the heteroaryl, heterocycloalkyl, C3-C6 cycloalkyl, C1-C6 alkynyl, C1-C6 alkoxy is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, OH, or heterocycloalkyl. or a pharma- ceutically acceptable salt thereof.

[0138] Also described herein is the following compound: [ka] TIFF2024541944000030.tif221148TIFF2024541944000031.tif196149TIFF2024541944000032.tif232148TIFF2024541944000033.tif226150TIFF2024541944000034.tif195148TIFF2024541944000035.tif226149TIFF2024541944000036.tif226148TIFF2024541944000037.tif192150TIFF2024541944000038.tif231149TIFF2024541944000039.tif207148TIFF2024541944000040.tif208148TIFF2024541944000041.tif205148TIFF2024541944000042.tif208149TIFF2024541944000043.tif230149TIFF2024541944000044.tif229148TIFF2024541944000045.tif222149TIFF2024541944000046.tif214149TIFF2024541944000047.tif226149TIFF2024541944000048.tif208151TIFF2024541944000049.tif209149TIFF2024541944000050.tif224149TIFF2024541944000051.tif201149TIFF2024541944000052.tif224151TIFF2024541944000053.tif227153TIFF2024541944000054.tif218149TIFF2024541944000055.tif233149TIFF2024541944000056.tif207152TIFF2024541944000057.tif200148TIFF2024541944000058.tif219148TIFF2024541944000059.tif225150TIFF2024541944000060.tif203149TIFF2024541944000061.tif229148TIFF2024541944000062.tif225148TIFF2024541944000063.tif230148TIFF2024541944000064.tif36148 or a pharma- ceutically acceptable salt thereof.

[0139] Also described herein is the following compound: [ka] TIFF2024541944000066.tif228149TIFF2024541944000067.tif210149TIFF2024541944000068.tif213149TIFF2024541944000069.tif203150TIFF2024541944000070.tif194149TIFF2024541944000071.tif205149TIFF2024541944000072.tif204149TIFF2024541944000073.tif199148TIFF2024541944000074.tif203149TIFF2024541944000075.tif233148TIFF2024541944000076.tif225149TIFF2024541944000077.tif221149TIFF2024541944000078.tif211147TIFF2024541944000079.tif215152TIFF2024541944000080.tif208148TIFF2024541944000081.tif232149TIFF2024541944000082.tif213149TIFF2024541944000083.tif213149TIFF2024541944000084.tif202148TIFF2024541944000085.tif232148TIFF2024541944000086.tif233148TIFF2024541944000087.tif236149TIFF2024541944000088.tif233148TIFF2024541944000089.tif224148TIFF2024541944000090.tif220149TIFF2024541944000091.tif223148TIFF2024541944000092.tif222150TIFF2024541944000093.tif198149TIFF2024541944000094.tif205147TIFF2024541944000095.tif197148TIFF2024541944000096.tif212149TIFF2024541944000097.tif204148TIFF2024541944000098.tif218149TIFF2024541944000099.tif230149TIFF2024541944000100.tif222149TIFF2024541944000101.tif212149TIFF2024541944000102.tif213153TIFF2024541944000103.tif34148 or a pharma- ceutical acceptable salt thereof.

[0140] definition The terms used herein have their usual meanings, and the meaning of such terms is independent at each occurrence. Nevertheless, and unless otherwise indicated, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. If a compound is referred to using both a chemical structure and a chemical name, and there is an ambiguity between the structure and the name, the structure shall prevail. These definitions apply regardless of whether the term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "C1-C6 alkyl" applies not only to "C1-C6 alkyl", but also to the "C1-C6 alkyl" moieties of "C1-C6 alkylaryl", "haloC1-C6 alkyl", "C1-C6 alkylheteroaryl", etc.

[0141] The term "alkoxy" refers to an alkyl-O- group, where the alkyl group includes straight chain alkyl having 1 to 10 carbon atoms and branched chain alkyl having 3 to 10 carbon atoms. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

[0142] An "effective amount" or "therapeutically effective amount" is intended to describe an amount of a compound or composition used in the methods of the invention that is effective to inhibit the above-described disease or enzymatic activity, and thus effective to produce the desired therapeutic, ameliorative, suppressive or prophylactic effect. For oral administration (e.g., capsule or tablet), an "effective amount" of a compound of the invention may span more than one capsule or tablet (so that a composition claim covers one tablet even if two tablets are required for effective administration).

[0143] The term "halogen" includes fluorine, chlorine, bromine or iodine.

[0144] The term “C1-C 16 The term "alkyl" includes linear alkyl having 1 to 6 carbon atoms and branched alkyl having 3 to 6 carbon atoms. Specific examples thereof 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, and 1-ethyl-1-methylpropyl.

[0145] The term "C3-C6 cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having 3 to 6 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0146] The term “C3-C 10"Cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having 3 to 10 carbons. "Cycloalkyl" also includes non-aromatic rings, and also includes monocyclic non-aromatic or aromatic rings fused to a saturated cycloalkyl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. Examples depicted in the structure include: [ka] etc.

[0147] The term "heteroaryl" means a mono- or polycyclic (including bicyclic) aromatic heterocycloalkyl containing at least one ring heteroatom selected from O, S, and N. Examples of heteroaryl groups include pyridyl (pyridinyl), oxazolyl, azabenzothiazole, benzothiazole, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl.

[0148] The term "heterocycloalkyl" means a monocyclic or bicyclic or bridged, partially unsaturated or saturated ring containing at least one heteroatom selected from N, S, and O, where each of the rings has 3 to 10 atoms and the point of attachment can be carbon or nitrogen. Examples include azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and dihydrocyclopentapyridinyl. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen, or N-substituted (1H,3H)-pyrimidine-2,4-diones (N-substituted uracils). 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, 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. Examples depicted in the structure are: [ka] etc.

[0149] The term "pharmacologically acceptable salts" refers to salts prepared from pharma- ceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term "pharmacologically acceptable salts" refer to non-toxic salts of the compounds of the present invention, generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothioate, lactate, lactobionate, laurate Acid salts include, but are not limited to, ammonium salts such as ammonium salts, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salts, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate. Additionally, when the compounds of the present invention contain an acidic moiety, suitable pharma- ceutically acceptable salts include those derived from inorganic bases, including, but not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.Salts derived from pharma- ceutically acceptable organic non-toxic bases include primary, 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, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0150] The term "patient" refers to a mammalian patient, preferably a human patient, undergoing or about to undergo medical treatment.

[0151] The compounds of the present invention may contain one or more asymmetric centers and may therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers, and the present invention is intended to encompass all such isomeric forms of these compounds.

[0152] Some of the compounds described herein contain olefinic double bonds, and, unless otherwise indicated, are meant to include both E and Z geometric isomers.

[0153] Some of the compounds described herein include substituted cycloalkanes that have cis- and trans isomers, and, unless otherwise indicated, are meant to include both the cis and trans geometric isomers.

[0154] The independent synthesis of these diastereomers or their chromatographic separation can be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized as necessary with a reagent containing an asymmetric center of known absolute configuration. If desired, the racemic mixture of the compound can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, for example, by coupling a racemic mixture of the compound to an enantiomerically pure compound to form diastereomers, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0155] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0156] It will be understood that the present invention is intended to encompass pharma- ceutically acceptable salts of the compounds described herein, and also to encompass non-pharmaceutically acceptable salts of the compounds described herein, when they are used as free compounds or precursors to pharma- ceutically acceptable salts, or used in other synthetic operations.

[0157] Solvates, and in particular, hydrates, of the compounds of the structural formulae described herein are also included in the present invention.

[0158] Some of the compounds described herein may exist as tautomers, which have different hydrogen attachment points accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers and mixtures thereof are encompassed by the compounds of the present invention.

[0159] In the compounds described herein, atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to encompass all suitable isotopic variations of the compounds represented by the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may confer certain therapeutic advantages, such as increased half-life in vivo or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. 3 H, 11 C. 18 Compounds labeled with F can be used for PET or SPECT or other imaging studies. Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents or intermediates.

[0160] It should be noted that chemically unstable compounds are excluded from the embodiments contained herein.

[0161] Treatment method The compounds described herein may be particularly useful for preventing, treating, or ameliorating RIPK1-mediated diseases or disorders that are believed to be controlled, at least in part, by programmed necrosis, apoptosis, or the production of inflammatory cytokines.

[0162] Compounds of the formulae described herein, or pharma- ceutically acceptable salts thereof, may be used to treat the following diseases or disorders mediated by RIPK1: 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, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome (APS), hematologic malignancies, and rheumatoid arthritis (HLA). ductitis, osteoarthritis, liver damage / disease, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen poisoning, hepatotoxicity), nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), kidney damage / injury (nephritis, kidney transplant, surgery, administration of nephrotoxic drugs (e.g., cisplatin), acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplanted organs, tissues, and cells) reaction), ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (Ml), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin I-converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke injury, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), tumors, melanoma, metastases, breast cancer, non-small cell lung cancer (NSCLC), radiation-induced necrosis, ischemic nephropathy, ophthalmic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, periodontitis, NEMO mutations (mutations in the NF-κ-B essential modulator gene (also known as IKKγ or IKKG)), especially NEMO deficiency syndrome,HOIL-1 deficiency (heme-oxidized IRP2 ubiquitin ligase-1 (also known as RBCK1) deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies, bacterial and viral infections (e.g. influenza, staphylococcus aureus and mycobacterium (tuberculosis)), and lysosomal storage diseases (particularly Gaucher disease, and other diseases such as GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 cancer, and others). It may be particularly useful in the treatment of: gliosidoses, mucolipidoses, childhood free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease), spinal cord injury, Stevens-Johnson syndrome, fibrosis, complement dependent cytotoxicity, toxic epidermal necrolysis, and / or in the treatment of cells ex vivo to maintain vitality and function.

[0163] Compounds of the formulae described herein, and their pharma- ceutically acceptable salts, may be useful in the treatment of glaucoma.

[0164] The compounds of the formulae described herein and their pharma- ceutically acceptable salts may be particularly useful in the treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma or melanoma.

[0165] The compounds represented by the formulas described herein and their pharma- ceutically acceptable salts may be particularly useful in the treatment of the following diseases or disorders mediated by RIPK1: rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), and psoriasis.

[0166] The treatment of the above-mentioned diseases / disorders may more particularly be related to the improvement of organ injury or damage suffered as a result of the above-mentioned diseases / disorders.For example, the compounds of the present invention may be particularly useful for improving brain tissue injury or damage after ischemic brain injury or traumatic brain injury, or for improving heart tissue injury or damage after myocardial infarction, or for improving brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or for improving liver tissue injury or damage associated with non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease or primary sclerosing cholangitis or acetaminophen overdose.The compounds of the present invention may be particularly useful for improving organ injury or damage suffered as a result of radiation therapy, or for improving spinal cord tissue injury or damage after spinal cord injury, or for improving liver tissue injury or damage associated with acute liver failure.The compounds of the present invention may be particularly useful for improving hearing impairment, such as noise-induced hearing loss, or hearing impairment after administration of ototoxic drugs or substances (e.g., cisplatin).

[0167] The compounds of the present invention (i.e., compounds of formula I, II, III, IV or V) may be particularly useful in ameliorating injury or damage to solid organ tissues (particularly kidney, liver, and heart and / or lung) following transplantation or administration of nephrotoxic drugs or substances (e.g., cisplatin). It is understood that amelioration of such tissue damage can be achieved, if possible, by pre-treatment with a compound of the formulas described herein or a pharma- ceutically acceptable salt thereof (e.g., by pre-treating the patient prior to administration of cisplatin or by pre-treating the organ or organ recipient prior to transplantation surgery). Amelioration of such tissue damage can be achieved by treatment with a compound of the formulas described herein or a pharma- ceutically acceptable salt thereof during transplantation surgery.

[0168] Amelioration of such tissue damage can also be achieved by treating the patient for a short period of time after transplant surgery with a compound of the formulas described herein, or a pharma- ceutically acceptable salt thereof.

[0169] In one embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.

[0170] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of multiple sclerosis.

[0171] In one embodiment, the compounds of the formulas described herein, and their pharma- ceutically acceptable salts, may be useful in the treatment of traumatic brain injury.

[0172] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of Huntington's disease or Niemann-Pick disease.

[0173] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of ALS, PSP, and Alzheimer's disease.

[0174] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of age-related macular degeneration.

[0175] The treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may more particularly relate to the amelioration of organ damage or injury suffered as a result of these diseases / disorders. For example, the compounds described herein may be particularly useful for ameliorating brain tissue damage or injury following traumatic brain injury, or for ameliorating brain tissue damage or injury associated with Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0176] In another embodiment, the compounds of the formulas described herein and pharma- ceutically acceptable salts thereof may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, as well as for ameliorating brain tissue injury or damage resulting from multiple sclerosis, traumatic brain injury, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

[0177] In another embodiment, the compounds of the formulae described herein and their pharma- ceutically acceptable salts may be useful in the treatment of Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis.

[0178] In yet another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of psoriasis, rheumatoid arthritis, and ulcerative colitis.

[0179] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of lupus, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.

[0180] In another embodiment, the compounds of the formulae described herein and their pharma- ceutical acceptable salts may be useful in the treatment of cerebrovascular accidents (CVA, stroke), Huntington's disease, Alzheimer's disease, ALS, traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.

[0181] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful for the treatment of ALS.

[0182] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of multiple sclerosis.

[0183] In another embodiment, the compounds of the formulae described herein and their pharma- ceutically acceptable salts may be useful in the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung cancer (NSCLC), and radiation-induced necrosis.

[0184] In another embodiment, the compounds of the formulae described herein and their pharma- ceutically acceptable salts may be useful in the treatment of PDAC, metastasis, melanoma, breast cancer and nNSCLC.

[0185] In another embodiment, the compounds of the formulas described herein, and pharma- ceutically acceptable salts thereof, may be useful for the treatment of PDAC.

[0186] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of intracerebral and subarachnoid hemorrhage.

[0187] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of type II diabetes and obesity.

[0188] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of atherosclerosis.

[0189] In another embodiment, the compounds of the formulas described herein, or pharma- ceutically acceptable salts thereof, may be useful for the treatment of vasculitis.

[0190] In another embodiment, the compounds of the formulae described herein and their pharma- ceutically acceptable salts may be useful in the treatment of dependent inflammation and cell death that occurs in genetic and sporadic diseases such as 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 injury caused by stroke, traumatic brain injury, encephalitis.

[0191] In another embodiment, the compounds of the formulae described herein and their pharma- ceutically acceptable salts may be useful in the treatment of ischemic renal damage, ophthalmic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0192] In another embodiment, the compounds of the formulas described herein and their pharma- ceutically acceptable salts may be useful in the treatment of non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).

[0193] The compounds of the present invention, particularly those represented by the formulas described herein and their pharma- ceutically acceptable salts, may be particularly useful for the treatment of cancer-related diseases or disorders mediated by RIPK1. Gong et al., The role of necroptosis in cancer biology and therapy, Molecular Cancer (2019) 18:100. In one embodiment, the human has a solid tumor. In one embodiment, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, NSCLC, prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one embodiment, the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, RCC, EC squamous cell carcinoma, non-small cell lung cancer, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another embodiment, the human has a liquid tumor, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, or chronic myeloid leukemia.

[0194] The present disclosure further relates to a method of treating or lessening the severity of a cancer selected from the following: brain (glioma), glioblastoma, astrocytoma, Banayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colorectal cancer, head and neck cancer (including head and neck squamous cell carcinoma), kidney cancer, lung cancer (including squamous cell carcinoma of the lung, adenocarcinoma of the lung, small cell carcinoma of the lung, and non-small cell lung cancer), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic carcinoma, squamous cell carcinoma of the lung, small cell carcinoma of the lung, and non-small cell lung cancer). cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic 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 megakaryocyte leukemia Myeloid 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 renal clear cell carcinoma, renal papillary carcinoma, and renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), and testicular cancer.

[0195] The cancer may be any cancer in which there is an abnormal number of blast cells or unwanted cell proliferation, or any cancer diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies.Myeloid malignancies include, but are not limited to, acute myeloid (or myeloblastic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyelocytic (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia, and megakaryocytic (or megakaryoblastic) leukemia.These leukemias may be collectively referred to as acute myeloid (or myeloblastic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), including, but not limited to, chronic myelogenous (or myelogenous) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndromes or MDS), which may also be referred to as refractory anemia (RA), refractory anemia with blasts (RAEB), and refractory anemia with blasts in transition (RAEBT), and myelofibrosis with or without primary myelofibrosis (MFS).

[0196] Specific examples of clinical conditions based on hematological neoplasms include leukemias, such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; lymphomas, such as non-Hodgkin's lymphoma and Hodgkin's lymphoma. Hematopoietic cancers also include lymphoid malignancies affecting lymph nodes, spleen, bone marrow, peripheral blood, and / or extranodal sites. Lymphoid cancers include B-cell malignancies, including, but not limited to, B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL can be low grade (or low-grade), intermediate grade (or aggressive), or high grade (highly aggressive). Low-grade B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including nodal 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 leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3, or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt's lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies further include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease.NHL also includes T-cell non-Hodgkin's lymphoma (T-NHL), which includes, but is not limited to, T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0197] Hematopoietic cancers also include Hodgkin lymphomas (or diseases), including classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocytopenic Hodgkin lymphoma. Hematopoietic cancers also include plasma cell disorders or cancers, such as multiple myeloma (MM), e.g., smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers can also include other cancers of additional hematopoietic cells, where such hematopoietic cells include polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as the spleen, lymph nodes, lymphoid tissues associated with mucosa (e.g., gut-associated lymphoid tissue), tonsils, Peyer's patches, and appendix, and lymphoid tissues associated with other mucosa, such as the bronchial lining.

[0198] Thus, in one aspect, the invention relates to a method of treating any of the RIPK1-mediated diseases or disorders described herein, comprising administering to a patient in need of such treatment an effective amount of a compound of Formula I, II, III, IV or V, or a pharma- ceutically acceptable salt thereof. In another embodiment, the method comprises administering to a patient in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of Formula I, II, III, IV or V, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0199] The present invention further relates to the use of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, or a pharma- ceutically acceptable salt thereof, for treating any of the diseases or disorders described herein in a patient in need of such treatment. In another embodiment, the present invention relates to the use of a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, for treating any of the diseases or disorders described herein in a patient in need of such treatment.

[0200] Pharmaceutical Compositions The compounds described herein can be administered orally or parenterally.When formulated into a dosage form suitable for administration, the compounds described herein can be used as pharmaceutical compositions for preventing, treating or ameliorating the above-mentioned diseases.

[0201] Thus, the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula I, II, III, IV or V as defined herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. The pharmaceutical composition may further comprise an effective amount of another active agent for the treatment of the same or different disease or disorder. In one embodiment, the additional therapeutic agent is effective against a disease or disorder mediated by RIPK1.

[0202] In the clinical use of the compounds described herein, the compounds can be generally formulated into various preparations together with pharma- ceutically acceptable additives according to the dosage form, and then administered. "Pharmaceutically acceptable" means that the additive, carrier, diluent or excipient must be compatible with the remaining components of the formulation and must not be harmful to the recipient. Thus, various additives that are generally used in the field of pharmaceutical preparations can be used. Specific examples include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminometasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid esters, polysorbates, sucrose fatty acid esters, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, and hydroxypropylcyclodextrin.

[0203] The preparations formed using these additives include, for example, the following: solid preparations, such as tablets, capsules, granules, powders, and suppositories; and liquid preparations, such as syrups, elixirs, and injections. These can be prepared according to conventional methods known in the field of pharmaceutical preparations. Liquid preparations can also be in a form that can be dissolved or suspended in water or other suitable medium when used.

[0204] In particular, in the case of injections, the preparations can be dissolved or suspended in physiological saline or glucose solution, to which buffers or preservatives can be added as needed.

[0205] The pharmaceutical composition may contain the compound of the present invention (i.e., a compound represented by any one of Formula I, II, III, IV, or V) in an amount of 1 to 99.9% by weight (preferably, 1 to 60% by weight) of the composition. The composition may further contain any other therapeutically effective compound.

[0206] When the compound of the present invention is used to prevent or treat the above diseases, the dosage and frequency of administration can be varied depending on the sex, age, body weight and condition of the patient, as well as the type and extent of the intended ameliorative effect. In general, in the case of oral administration, the dosage can be 0.001 to 50 mg / kg body weight / day, and it can be administered at once or in several divided doses. In a specific embodiment, the dosage is about 0.01 to about 25 mg / kg / day, and in a specific embodiment, about 0.05 to about 10 mg / kg / day. In the case of oral administration, the composition is preferably provided in the form of a tablet or capsule containing 0.01 mg to 1,000 mg. In certain embodiments, 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 a compound described herein. This dosage regimen can be adjusted to provide the optimal therapeutic effect.

[0207] Combination therapy The compounds of the invention are further useful in methods of preventing or treating the above-mentioned diseases, disorders and conditions in combination with other therapeutic agents.

[0208] The compounds of the present invention can be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds described herein or the other drugs may be useful, where the combination of drugs taken together is safer or more effective than either drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds described herein or their pharmaceutically acceptable salts in amounts commonly used. When the compounds described herein are used simultaneously with one or more other drugs, in certain embodiments, the pharmaceutical composition can include such other drugs and the compounds described herein or their pharmaceutically acceptable salts in unit dosage form. However, the combination therapy can also include therapies in which the compounds described herein or their pharmaceutically acceptable salts and one or more other drugs are administered on 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 the other active ingredients can be used in lower doses than when each is used alone. Thus, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds described herein or their pharmaceutically acceptable salts.

[0209] Abbreviation The abbreviations used herein have the meanings set out in the table below. Abbreviations not set out in the table below have their commonly used meanings unless otherwise specified. [Table 1] TIFF2024541944000107.tif193169 EXAMPLES

[0210] General synthesis scheme General synthetic scheme I [ka] Starting from the racemic amino alcohol I, the amine can be coupled with the corresponding hydroxy acid II. The pendant primary alcohol can be oxidized to the aldehyde III, which undergoes ring closure under mildly acidic conditions. The enantiomeric mixture can be separated using chiral SFC chromatography (or transferred to the unprotected piperidine, if previously resolved) to give the desired (5'S,7a'R) enantiomer. Finally, the protecting groups can be removed under strong acidic conditions to give the unprotected amine V.

[0211] General synthetic scheme II [ka] Spiroamino functionalization to introduce aryl and heteroaryl moieties can be carried out on a large scale using conventional SnAr conditions. In a polar aprotic solvent such as DMA or DMF, base is added and the mixture is heated to completion. Palladium (Pd) cross-coupling conditions have been established when SnAr chemistry is not feasible. Both approaches can be implemented in a library format.

[0212] General synthetic scheme III [ka] The spiro amino can be reacted with a variety of carbonyl acid reagents to give disubstituted amides using standard (peptide) coupling procedures, depending largely on the availability of the acid coupling moiety. [ka] The carboxylated or activated ester derivatives of the core can be derivatized using innovations in Ni / photoredox cross-coupling and / or reductive electrophilic cross-coupling to give the corresponding arylated compounds.

[0213] Intermediates Intermediate I-1. Preparation of (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one hydrochloride [ka] Step 1. (R,E)-N-(3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide Titanium(IV) isopropoxide (525 g, 1.85 mol) and (R)-2-methylpropane-2-sulfinamide (194 g, 1.60 mol) were added to a solution of 3,5-difluorobenzaldehyde (175 g, 1.23 mol) in toluene (3000 mL) at 20 °C. The reaction mixture was stirred at 50 °C for 12 h. Saturated aqueous NaHCO3 (1000 mL) was added to the reaction and the resulting suspension was filtered through Celite. The filter cake was washed with EtOAc (500 mL) and the filtrate was separated into organic and aqueous layers. The aqueous layer was extracted with EtOAc (500 mL x 3), then the combined organic layers were washed with brine (1000 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1) to give (R,E)-N-(3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide.

[0214] Step 2. (R)-N-((S)-1-(3,5-difluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide Zinc (213 g, 3.27 mol), indium(III) trifluoromethanesulfonate (1020 g, 1.82 mol) and 3-bromoprop-1-ene (146 g, 1.21 mol) were added to a stirred mixture of (R,E)-N-(3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (298 g, 1.21 mol) in THF (2970 mL) at 20° C. The reaction mixture was stirred at 20° C. for 12 h. The reaction was diluted with EtOAc (2000 mL), washed with brine (1000 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=5:1) to give (R)-N-((S)-1-(3,5-difluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide.

[0215] Step 3. (R)-N-((S)-1-(3,5-difluorophenyl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(3,5-difluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (334 g, 1.16 mol) was reacted with 9-BBN (0.5 M solution in THF; 6.96 L, 3.48 mol) at 0° C. and allowed to warm slowly to room temperature over 3 h until all starting material was consumed. The reaction mixture was cooled to 0° C. and hydrogen peroxide (30% aqueous solution; 1.2 L, 11.6 mol) was added dropwise, followed by NaOH (8.82 M aqueous solution; 1.3 L, 11.6 mol). The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched by the addition of water (2 L) and extracted with ethyl acetate (3×1 L). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc / hexanes=60:40) to give (R)-N-((S)-1-(3,5-difluorophenyl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide.

[0216] Step 4. (S)-4-amino-4-(3,5-difluorophenyl)butan-1-ol, HCl A solution of (R)-N-((S)-1-(3,5-difluorophenyl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide (178 g, 579 mmol) in HCl (1.77 L, 4 M solution in methanol) was stirred at 30° C. for 1 h. The reaction mixture was concentrated under reduced pressure. Water (300 mL) was added to the crude residue, followed by saturated aqueous NaHCO3 until pH was 8. The solution was extracted with EtOAc (100 mL×3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (S)-4-amino-4-(3,5-difluorophenyl)butan-1-ol, HCl.

[0217] MS (ESI) m / z C 10 H 14 ClF2NO [M+H] + Calculated 202, Measured 202. 1H NMR (400 MHz, CDCl3) δ 6.86 (d, J = 6.6 Hz, 2H), 6.70 (t, J = 8.8 Hz, 1H), 3.87 - 4.05 (m, 1H), 3.67 (d, J = 13.5 Hz, 2H), 2.27 (s, 3H), 1.78 - 1.97 (m, 1H), 1.57 - 1.78 (m, 3H). The compounds shown in Table 1 were prepared following the synthetic route of intermediate I-1 using procedures similar to those described above. [Table 2] Intermediate I-5. Preparation of (S)-1-(4-fluorophenyl)but-3-en-1-amine [ka] Step 1. (R,Z)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfinamide Titanium(IV) isopropoxide (17.2 g, 60.4 mmol) was added to a solution of 4-fluorobenzaldehyde (5.0 g, 40 mmol) and (R)-2-methylpropane-2-sulfinamide (6.35 g, 52.4 mmol) in dry THF (100 mL) at room temperature. The reaction mixture was stirred and heated at 50 °C for 1 h. To the reaction was added saturated aqueous sodium chloride (70 mL). The mixture was diluted with H2O (50 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAC (80 mL x 3) and washed with saturated aqueous sodium chloride (50 mL x 2). The organic layer was collected, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO SiO2 40 g; ethyl acetate in petroleum ether 0-5%) to give (R,Z)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfinamide.

[0218] MS (ESI) m / z C 11 H 15 FNOS [M+H] + Calculated 228, Measured 228. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.07 - 7.98 (m, 2 H), 7.38 (t, J = 8.8 Hz, 2 H), 1.18 (s, 9 H). Step 2. (R)-N-((S)-1-(4-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide To a stirred solution of (R,Z)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.0 g, 8.8 mmol), indium(III) trifluoromethanesulfonate (7.42 g, 13.2 mmol), and zinc (1.15 g, 17.6 mmol) in THF (50 mL) was added 3-bromoprop-1-ene (2.13 g, 17.6 mmol) at room temperature. The mixture was stirred for 16 h and quenched with brine (100 mL). The mixture was extracted with EtOAc (60 mL x 3) and the combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO SiO2 40 g; ethyl acetate in petroleum ether, 0-45%) to give (R)-N-((S)-1-(4-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide.

[0219] MS (ESI) m / z C 14 H 21 FNOS [M+H] + Calculated 270, Measured 270. Step 3. (S)-1-(4-fluorophenyl)but-3-en-1-amine HCl / MeOH (4M) (20 mL) was added in one portion to (R)-N-((S)-1-(4-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.49 g, 5.53 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure, water (10 mL) was added to the residue and the pH was adjusted to neutral with 1 M NaOH solution. The mixture was diluted with EtOAc (25 mL) and the organic layer was separated. The aqueous solution was extracted again with EtOAc (20 mL x 3) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give (S)-1-(4-fluorophenyl)but-3-en-1-amine.

[0220] MS (ESI) m / z C 10 H 13 FN [M+H] + Calculated 166, Measured 166. Each of the synthetic amines shown in Table 2 below were prepared using procedures similar to those described above following the synthetic route of intermediate I-5. [Table 3] TIFF2024541944000116.tif36161 Intermediate I-13. Preparation of 7-chloro-3-fluoropyrazolo[1,5-a]pyrimidine [ka] Step 1. Ethyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate A 20 L round bottom flask, purged with and maintained under an inert atmosphere of nitrogen, was charged with 1H-pyrazol-5-amine (400 g, 4.82 mol), acetic acid (20 L, 349 mol), and 1,3-diethyl 2-(ethoxymethylidene)propanedioate (2080 g, 9.62 mol). The resulting solution was stirred in an oil bath at 130° C. for 12 hours. The solid was collected by filtration and washed with EtOH to give ethyl 7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate.

[0221] Step 2. 7-Oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid A 5000 mL round bottom flask, purged with and maintained under an inert atmosphere of nitrogen, was charged with a solution of ethyl 7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylate (550 g, 2657 mmol, 1.00 equiv.) in ethanol (2750 mL) and a solution of sodium hydroxide (275 g, 6875 mmol, 2.50 equiv.) in water (2500 mL). The resulting solution was stirred at 90° C. in an oil bath for 12 hours. The solid was collected by filtration. The resulting solid was dissolved in 2500 mL of water and to it was added 1500 g of citric acid. The solid was collected by filtration and washed with HO. This provided 460 g of 7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid.

[0222] Step 3. Pyrazolo[1,5-a]pyrimidin-7-ol A 10 L round bottom flask, purged with and maintained under an inert atmosphere of nitrogen, was charged with 7-oxo-4H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (460 g, 2.57 mol) and phenoxybenzene (3795 mL, 23.9 mol). The resulting solution was stirred at 250° C. for 12 hours. The solid was collected by filtration, washed with n-hexane, and concentrated to give pyrazolo[1,5-a]pyrimidin-7-ol.

[0223] Step 4. 7-Chloropyrazolo[1,5-a]pyrimidine A 5000 mL round bottom flask, purged with and maintained under an inert atmosphere of nitrogen, was charged with phosphoroyl trichloride (1406 g, 9170 mmol), pyrazolo[1,5-a]pyrimidin-7-ol (340 g, 1058 mmol) and DIEA (468 g, 3527 mmol). The resulting solution was stirred at 90° C. for 4 hours. The resulting solution was poured into ice water and the solution was extracted with dichloromethane (1000 mL×3). The organic layers were combined and concentrated under reduced pressure to provide 7-chloropyrazolo[1,5-a]pyrimidine.

[0224] Step 5. 7-Chloro-3-fluoropyrazolo[1,5-a]pyrimidine (I-13) A mixture of 7-chloropyrazolo[1,5-a]pyrimidine (250 g, 1.63 mol) in MeCN (5000 mL) was added to a 10 L 3-neck round bottom flask that had been purged with and maintained under an inert atmosphere of nitrogen. Selectfluor (694 g, 1.96 mol) was stirred at 25° C. for 16 h. The mixture was poured into water (3000 mL) and extracted with EtOAc (1000 mL×3). The combined organic phases were dried (Na2SO4), filtered, and concentrated under pressure. The crude product was purified by reverse phase chromatography (eluting with 20%→45% MeCN / water). The product was concentrated under reduced pressure to give 7-chloro-3-fluoropyrazolo[1,5-a]pyrimidine.

[0225] MS (ESI) m / z C6H4ClFN3[M+H] + Calculated 172, Measured 172. 1 H NMR (400MHz, CDCl3), δ 8.42 - 8.39 (m, 1H), 8.24 - 8.18 (m, 1H), 7.06 - 7.01 (m, 1H). Intermediate I-14A and Intermediate I-14B. Preparation of 1-(tert-butyl) 4-methyl (3[R and S], 4[S and R])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate and 1-(tert-butyl) 4-methyl (3[R and S], 4[R and S])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate [ka] Step 1. tert-Butyl 4-cyano-3-methyl-4-((trimethylsilyl)oxy)piperidine-1-carboxylate A solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (15.0 g, 70.3 mmol) in trimethylsilyl cyanide (60 mL) was cooled to 0° C. and treated with ZnI2 (0.673 g, 2.11 mmol). The resulting mixture was stirred at 20° C. for 16 h. The reaction solution was directly concentrated under reduced pressure to give tert-butyl 4-cyano-3-methyl-4-((trimethylsilyl)oxy)piperidine-1-carboxylate, which was used in the next reaction without further purification.

[0226] Step 2. Synthesis of methyl 4-hydroxy-3-methylpiperidine-4-carboxylate A solution of tert-butyl 4-cyano-3-methyl-4-((trimethylsilyl)oxy)piperidine-1-carboxylate (18.3 g, 58.7 mmol) in HCl (4 M in MeOH, 300 mL) was stirred at 60° C. for 2 h. After cooling, the reaction mixture was directly concentrated under reduced pressure to give methyl 4-hydroxy-3-methylpiperidine-4-carboxylate, which was used in the next reaction without further purification.

[0227] MS (ESI) m / z C8H 16 NO3[M+H] + Calculated 174, Measured 174. Step 3. Preparation of 1-(tert-butyl) 4-methyl (3[R and S], 4[S and R])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate (I-14A) and 1-(tert-butyl) 4-methyl (3[R and S], 4[R and S])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate (I-14B) A mixture of methyl 4-hydroxy-3-methylpiperidine-4-carboxylate (12.0 g, 69.3 mmol) in DCM (350 mL) was treated with triethylamine (48.3 mL, 346 mmol) and Boc2O (32.2 mL, 139 mmol). The resulting mixture was stirred at 20° C. for 3 h. The reaction was partitioned with EtOAc (400 mL) and water (400 mL) and then extracted with EtOAc (400 mL×2). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / petroleum ether, 0-20%) to give 1-(tert-butyl) 4-methyl (3[R and S],4[S and R])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate as the first eluting peak and 1-(tert-butyl) 4-methyl (3[R and S],4[R and S])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate as the second eluting peak.

[0228] MS (ESI) m / z C8H 16 NO3[M+H-100] + Calculated 174, Measured 174. The synthesized hydroxy-esters shown in Table 3 below were prepared as the second eluting peak using procedures similar to those described above following the synthetic route for Intermediate I-14A and Intermediate I-14B. [Table 4] Intermediate I-15A. Preparation of (3[R and S],4[R and S])-1-(tert-butoxycarbonyl)-4-hydroxy-3-methylpiperidine-4-carboxylic acid [ka] A mixture of 1-(tert-butyl) 4-methyl (3[R and S],4[R and S])-4-hydroxy-3-methylpiperidine-1,4-dicarboxylate (6.0 g, 22.0 mmol) in THF (108 mL) and water (36 mL) was treated with LiOH (1.58 g, 65.9 mmol). The resulting mixture was stirred at 25 °C for 12 h. The reaction was partitioned between EtOAc (150 mL) and water (200 mL) and the aqueous layer was acidified with 2 M HCl until pH 4. The aqueous layer was then extracted with EtOAc (150 mL x 2). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give (3[R and S],4[R and S])-1-(tert-butoxycarbonyl)-4-hydroxy-3-methylpiperidine-4-carboxylic acid.

[0229] 1 H NMR (400 MHz, MeOD-d4) δ 3.72 - 3.63 (m, 1H), 3.61 - 3.54 (m, 1H), 3.45 (br s, 2H), 2.07 - 1.97 (m, 1H), 1.89 - 1.79 (m, 1H), 1.63 - 1.53 (m, 1H), 1.46 (s, 9H), 0.93 (d, J = 6.8 Hz, 3H). The synthesized hydroxy-acids shown in Table 4 below were prepared using procedures similar to those described above following the synthetic route for intermediate I-15A. [Table 5] Intermediate I-16. Preparation of (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[azetidine-3,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] Step 1. tert-Butyl 3-((1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-3-hydroxyazetidine-1-carboxylate 1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid (366 mg, 1.68 mmol), 4-amino-4-(3,5-difluorophenyl)butan-1-ol, HCl (I-1, racemic) (400 mg, 1.68 mmol) and HATU (672 mg, 1.77 mmol) in dry acetonitrile (16.8 mL) were added to a 250 mL flask. The mixture was cooled to 0° C. and then triethylamine (0.469 mL, 3.37 mmol) was added in one portion. The mixture was stirred overnight and allowed to warm to room temperature. The mixture was concentrated and the residue was purified on an ISCO SiO2 24 g column (3:1 ethyl acetate / EtOH in hexanes, 20-60%). The desired fractions were combined and the volatiles were evaporated to give tert-butyl 3-((1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-3-hydroxyazetidine-1-carboxylate.

[0230] MS (ESI) m / z C 19 H 26 F2N2NaO5[M+Na] + Calculated 423, Measured 423. Step 2. tert-Butyl 3-((1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-3-hydroxyazetidine-1-carboxylate tert-Butyl 3-((1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-3-hydroxyazetidine-1-carboxylate (815 mg, 2.03 mmol) was added to a 100 mL flask and dissolved in DCM (20 mL) under argon. The mixture was cooled to 0° C. and DMP (1.38 g, 3.26 mmol) was added in one portion. The mixture was stirred at 0° C. for 60 min. The mixture was diluted with DCM (20 mL), quenched with saturated aqueous Na2S2O3 (5 mL) and stirred vigorously for 10 min. The organics were washed with saturated aqueous NaHCO3 (15 mL), then with brine (15 mL) and collected. The organics were dried (MgSO4), filtered and concentrated to give tert-butyl 3-((1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-3-hydroxyazetidine-1-carboxylate, which was carried on without further purification.

[0231] MS (ESI) m / z C 19 H 24 F2N2NaO5[M+Na] + Calculated 421, Measured 421. Step 3. tert-Butyl 5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[azetidine-3,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate To the crude tert-butyl 3-((1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-3-hydroxyazetidine-1-carboxylate (811 mg, 2.03 mmol) dissolved in dry toluene (20.3 mL) was added TsOH (136 mg, 0.71 mmol) in one portion at room temperature. The mixture was heated to 75° C. and stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography (ISCO SiO2 12 g; ethyl acetate in hexanes, 10-60%). The desired fractions were combined and the volatiles were evaporated to give tert-butyl 5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[azetidine-3,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate as a mixture of enantiomers. This material was subjected to chiral SFC chromatography (Lux-4, 21×250 mm, 5 um; modifier: 20% MeOH (containing 0.1% NH4OH), 70 mL / min). Peak 2 was collected and concentrated to give the desired enantiomer.

[0232] MS (ESI) m / z C 19 H 22 F2N2NaO4[M+Na] + Calculated value 403, measured value 403. Step 4. (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[azetidine-3,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-16) tert-Butyl (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[azetidine-3,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (150 mg, 0.394 mmol) in DCM and TFA (30 μL, 0.39 mmol) were added to the vial at room temperature. The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure to give (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[azetidine-3,2'-pyrrolo[2,1-b]oxazole]-3'-one, which was carried forward in crude form.

[0233] MS (ESI) m / z C 14 H15 F2N2O2[M+H] + Calculated 281, Measured 281. Each of the synthesized azetidines shown in Table 5 below was prepared using procedures similar to those described above following the synthetic route of intermediate I-16. [Table 6] Intermediate I-17. Preparation of (3'R,7a'S)-3'-phenyltetrahydro-5'H-spiro[piperidine-4,6'-pyrrolo[2,1-b]oxazol]-5'-one, hydrochloride [ka] Step 1. 1-(tert-butyl) 4-methyl 4-allylpiperidine-1,4-dicarboxylate Lithium diisopropylamide (6.17 mL, 12.3 mmol) was added to a solution of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2.0 g, 8.2 mmol) in THF (30 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min. A solution of 3-bromoprop-1-ene (1.49 g, 12.3 mmol) in THF (5 mL) was added dropwise and the mixture was stirred at 0 °C for 5 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO SiO2 20 g; EtOAC in petroleum ether 0-20%) to give 1-(tert-butyl) 4-methyl 4-allylpiperidine-1,4-dicarboxylate.

[0234] Step 2. 1-(tert-butyl) 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate A solution of 1-(tert-butyl) 4-methyl 4-allylpiperidine-1,4-dicarboxylate (2.0 g, 7.1 mmol) in DCM (40 mL) was bubbled with O3 for 20 min at -78° C. Triphenylphosphine (2.22 g, 8.47 mmol) was added in one portion and the mixture was stirred at 20° C. for 3 h. The mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO SiO2 20 g; EtOAC 0-20% in petroleum ether) to give 1-(tert-butyl) 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate.

[0235] 1 H NMR (400 MHz, CDCl3) δ 9.72 (s, 1 H), 3.72, (s, 3 H), 3.68 - 3.66 (m, 2 H), 3.24 - 3.18 (m, 2 H), 2.70 (s, 2 H), 2.13 - 2.10 (m, 2 H), 1.54 - 1.49 (m, 2 H), 1.45 (s, 9 H). Step 3. tert-Butyl (3'R,7a'S)-5'-oxo-3'-phenyltetrahydro-5'H-spiro[piperidine-4,6'-pyrrolo[2,1-b]oxazole]-1-carboxylate A mixture of 1-(tert-butyl) 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (1.30 g, 4.56 mmol) and (R)-2-amino-2-phenylethan-1-ol (0.625 g, 4.56 mmol) in MeCN / AcOH=20:1 (22 mL) (v / v) was stirred for 16 h at 80° C. The mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO SiO2 20 g; EtOAC 0-20% in petroleum ether) to give tert-butyl (3'R,7a'S)-5'-oxo-3'-phenyltetrahydro-5'H-spiro[piperidine-4,6'-pyrrolo[2,1-b]oxazole]-1-carboxylate.

[0236] MS (ESI) m / z C 21 H 29 N2O4[M+H-56] + Calculated 317, measured 371. Step 4. (3'R,7a'S)-3'-Phenyltetrahydro-5'H-spiro[piperidine-4,6'-pyrrolo[2,1-b]oxazol]-5'-one, HCl (I-17) A mixture of tert-butyl (3'R,7a'S)-5'-oxo-3'-phenyltetrahydro-5'H-spiro[piperidine-4,6'-pyrrolo[2,1-b]oxazole]-1-carboxylate (1.30 g, 3.49 mmol) in 4M HCl in dioxane (15 mL) was stirred for 2 h at 20° C. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (instrument EH, C18 150*25 mm*5 um, condition water (NH4HCO3)-ACN, start B 20, end B 50, (gradient time (min) 10 100% B, retention time (min) 2) to give (3'R,7a'S)-3'-phenyltetrahydro-5'H-spiro[piperidine-4,6'-pyrrolo[2,1-b]oxazole]-5'-one, HCl.

[0237] MS (ESI) m / z C 16 H 21 N2O2[M+H] + Calculated 273, Measured 273. Intermediate I-18. Preparation of 5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one [ka] Step 1. 5-(3,5-difluorophenyl)pyrrolidin-2-one Isopropylmagnesium chloride lithium chloride complex (97 mL, 126 mmol) was added to a solution of 1-bromo-3,5-difluorobenzene (14.6 g, 76 mmol) in THF (110 mL) at 0° C. The mixture was heated at 50° C. for 1 h, cooled to −78° C., and a solution of pyrrolidine-2,5-dione (5.0 g, 51 mmol) in DCM (5 mL) was added. The mixture was stirred at 25° C. for 16 h. Sodium cyanoborohydride (3.81 g, 60.6 mmol) was added to the resulting mixture at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction was acidified with HCl (6 M) to pH=3-4 (at 0° C.), stirred at room temperature for 30 min, and neutralized with aqueous NaOH (3 M). The reaction was partitioned between DCM (600 mL) and water (2 L). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / hexanes, 0-100%) to give 5-(3,5-difluorophenyl)pyrrolidin-2-one.

[0238] MS (ESI) m / z C 10 H 10 F2NO [M+H] + Calculated 198, Measured 198. Step 2. 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole Dimethyloxonium tetrafluoroborate (1.8 g, 13.2 mmol) was added to a solution of 5-(3,5-difluorophenyl)pyrrolidin-2-one (2.0 g, 10.1 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at 25° C. for 16 h. The mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with DCM (20 mL×3). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 2-(3,5-difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole.

[0239] MS (ESI) m / z C 11 H 12 F2NO [M+H] + Calculated 212, Measured 212. Step 3. tert-Butyl 5'-(3,5-difluorophenyl)-3'-oxo-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazole]-1-carboxylate 2-(3,5-Difluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (2.9 g, 9.6 mmol) was added to a solution of 1-(tert-butyl) 4-methyl 4-aminopiperidine-1,4-dicarboxylate (2.73 g, 10.6 mmol) in n-BuOH (40 mL) at 20° C. The mixture was stirred at 120° C. for 30 h. The reaction was cooled to room temperature and partitioned with ethyl acetate (100 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (80 mL×2) and the combined organic layers were washed with brine (250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA) and then repurified by flash silica gel chromatography (0-5% MeOH / DCM) to give tert-butyl 5'-(3,5-difluorophenyl)-3'-oxo-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazole]-1-carboxylate.

[0240] MS (ESI) m / z C 21 H 25 F2N3O3[M+H] + Calculated value 406, measured value 406. Step 4. 5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one (I-18) TFA (2 mL) was added to a solution of tert-butyl 5'-(3,5-difluorophenyl)-3'-oxo-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-1-carboxylate (280 mg, 0.552 mmol) in DCM (6 mL) at 20° C. The mixture was stirred at 20° C. for 2 h. The mixture was concentrated to give 5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one (racemic).

[0241] MS (ESI) m / z C 16 H 17 F2N3O [M+H] +Calculated 306, Measured 306. Intermediate I-19. Preparation of 1-(2-bromopyridin-4-yl)-5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one [ka] 2-Bromo-4-fluoropyridine (9.2 mg, 0.052 mmol) and Cs2CO3 (25.6 mg, 0.079 mmol) were added to a solution of 5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one (10 mg, 0.026 mmol) in t-aminol alcohol (0.5 mL). The mixture was stirred at 100 °C under N2 for 16 h. LCMS showed the desired product was formed. The mixture was filtered and the filtrate was concentrated to give a residue. This was purified by preparative HPLC (instrument ed; Method Column BostonPrime C18 150 mm x 30 mm x 5 μm; Conditions Water (0.05% NH3 / H2O + 10 mM NH4HCO3)-ACN (Gradient time 10 min); 100% B retention time (min) 2 Flow rate (mL / min) 25; Injection 1) to give 1-(2-bromopyridin-4-yl)-5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one.

[0242] MS (ESI) m / z C 21 H 19 BrF2N4O [M+H] + Calculated value 461, measured values ​​461 and 463. 1H NMR (400 MHz, methanol-d4) δ 7.89 (d, J = 6.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.97-6.83 (m, 4H), 5.07 (dd, J = 5.2, 8.0 Hz, 1H), 3.96 (br d, J =14.0 Hz, 2H), 3.47 (br t, J = 10.8 Hz, 2H), 3.03-2.66 (m, 3H), 2.28-2.45 (m, 1H), 1.92-2.04 (m, 2H), 1.68-1.83 (m, 2H). Preparation of Intermediate I-20. (5'S,7a'R)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA [ka] Step 1. (S)-4-((1-(4-fluorophenyl)but-3-en-1-yl)carbamoyl)-4-hydroxypiperidine-1-carboxylate To a stirred solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid (2.01 g, 8.21 mmol) in DMF (10 mL) was added TEA (2.29 mL, 16.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.57 g, 8.21 mmol) and HOBT (1.26 mg, 8.21 mmol) at room temperature. (S)-1-(4-fluorophenyl)but-3-en-1-amine (904 mg, 5.47 mmol, I-5) was added in one portion and stirred for 17 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO SiO2 80 g; 0-50% ethyl acetate in petroleum ether) to give tert-butyl (S)-4-((1-(4-fluorophenyl)but-3-en-1-yl)carbamoyl)-4-hydroxypiperidine-1-carboxylate.

[0243] MS (ESI) m / z C 21 H 30 FN2O4[M+1-Boc] calculated 293, found 293. Step 2. tert-Butyl 4-((2S)-2-(4-fluorophenyl)-5-hydroxypyrrolidine-1-carbonyl)-4-hydroxypiperidine-1-carboxylate To a stirred mixture of silver nitrate (2.35 mg, 0.015 mmol) in t-butanol (3 mL) and nitromethane (0.2 mL) was added copper(II) chloride (4.1 mg, 0.031 mmol) and bis(benzonitrile)palladium chloride (11.7 mg, 0.031 mmol). The mixture was stirred at room temperature for 5 min. Rac-tert-butyl (R)-4-((1-(4-fluorophenyl)but-3-en-1-yl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (100 mg, 0.255 mmol) was added in one portion and the mixture was stirred at room temperature for 40 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude tert-butyl (S)-4-((1-(4-fluorophenyl)-4-oxobutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate, which was not further purified.

[0244] MS (ESI) m / z C 21 H 30 FN2O5[M+H] + Calculated 409, Measured 409. Step 3. (5'S,7a'R)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA (I-20) A solution of tert-butyl (R)-4-((1-(4-fluorophenyl)-4-oxobutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (200 mg, 0.490 mmol) in MeCN (3 mL) was heated to 80° C. Then methanesulfonic acid (141 mg, 1.47 mmol) was added at 80° C. The resulting mixture was stirred at 80° C. for 16 hours. The residue was purified by Prep-HPLC (Instrument Method Column Phenomenex Synergi (C18 150×21.2 mm×4 um) water (0.1% TFA)-MeCN) to give (5′S,7a′R)-5′-(4-fluorophenyl)tetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-3′-one, TFA as a brown solid.

[0245] MS (ESI) m / z C 16 H 20FN2O2[M+1] + Calculated 291, Measured 291. Each of the synthesized piperidines shown in Table 6 below was prepared using procedures similar to those described above following the synthetic route of intermediate I-20. [Table 7] Intermediate I-21. Preparation of (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, hydrochloride [ka] Step 1. tert-Butyl 4-((1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate Triethylamine (265 g, 2.40 mmol) was added dropwise to a solution of (S)-4-amino-4-(3,5-difluorophenyl)butan-1-ol (239 g, 1.00 mol, I-1), 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid (291 g, 1.19 mmol) and HATU (474 ​​g, 1.20 mmol) in acetonitrile (5800 mL) at 0-10° C. The reaction mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by silica chromatography (dichloromethane / methanol 40:1-20:1) to give tert-butyl 4-((1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate.

[0246] Step 2. tert-Butyl (S)-4-((1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (I-21.1) To a solution of tert-butyl (S)-4-hydroxy-4-((4-hydroxy-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate (407 g, 951 mmol) and pyridine (75 g, 950 mmol) in methylene chloride (4068 mL) was added 1,1-bis(acetyloxy)-3-oxo-1,5,2-benzoiodaxol-1-yl acetate (604 g, 1.42 mol) in portions at 0-10° C. The reaction mixture was stirred at 25° C. for 12 h. The reaction was quenched with saturated aqueous Na2S2O3 (3 L) and then washed with saturated aqueous NaHCO3 (2×3000 mL) and water (2×3000 mL). The organic layer was then dried (Na2SO4) and filtered. The filtrate was then concentrated under reduced pressure to give tert-butyl (S)-4-((1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate.

[0247] Step 3. tert-Butyl (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate A solution of tert-butyl (S)-4-((1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (239 g, 561 mmol) and TsOH (48 g, 279 mmol) in toluene (2389 mL) was stirred at 50° C. for 12 h. The reaction mixture was diluted with ethyl acetate (2000 mL) and the organic layer was washed with saturated aqueous NaHCO (2×1500 mL) and water (3×1500 mL). The organic layer was dried (NaSO), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica chromatography (petroleum ether / ethyl acetate 2:1) to give tert-butyl (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate.

[0248] MS (ESI) m / z C 21 H 26 F2N2NaO4[M+Na] +Calculated 431, Measured 431. Step 4. (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one hydrochloride (1-21) A solution of tert-butyl (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (73.9 g, 1.00 equiv) in HCl (739 mL, 4.0 M solution in 1,4-dioxane) was stirred for 3 h at 25° C. The reaction was filtered and the collected solid was washed with diethyl ether (3×100 mL) and then dried (Na2SO4) to give (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-3'-one, HCl.

[0249] MS (ESI) m / z C 16 H 19 F2N2O2[M+H] + Calculated 309, Measured 309. 1 H-NMR (400MHz, D2O) δ 6.91 - 6.76 (m, 3H), 5.83 (dd, J = 7.9, 5.0 Hz, 1H), 4.95 (t, J = 8.1 Hz, 1H), 3.50 - 3.37 (m, 2H), 3.28 (td, J = 12.6, 3.5 Hz, 1H), 3.17 (td, J = 12.8, 3.6 Hz, 1H), 2.71 (dtd, J = 13.2, 7.6, 1.9 Hz, 1H), 2.35 - 2.21 (m, 2H), 2.24 - 2.11 (m, 1H), 2.08 - 1.89 (m, 3H), 1.75 (tt, J = 12.0, 7.8 Hz, 1H). Each compound shown in Table 7 below was prepared using procedures similar to those described above, following the synthetic route of intermediate I-21 and using combinations of intermediates in Table 1, I-15A-C and I-29. [Table 8] Intermediate I-22. (5'S,7a'R)-5'-Phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]thiazol]-3'-one [ka] Step 1. 1-(tert-butyl) 4-methyl 4-((4-methoxybenzyl)thio)piperidine-1,4-dicarboxylate Under an argon atmosphere, diisopropylamine (5.86 mL, 41.1 mmol) was added to THF (50.0 mL) and cooled to -70°C. Lithium diisopropylamide (17.8 mL, 26.7 mmol, 1.6 M) in THF was then added and the mixture was warmed to -5°C and then cooled back to -75°C. A solution of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (5.0 g, 20.6 mmol) in THF (12.5 mL) was added and the mixture was stirred at -25°C for 1 hour. 1,2-bis(4-methoxybenzyl)disulfane (6.30 g, 20.55 mmol) was added to THF (12.5 mL) over 5 minutes and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL) and saturated sodium bicarbonate (100 mL), dried (over Na2SO4) and evaporated. The crude was purified by silica gel chromatography (ethyl acetate / hexanes) to give 1-(tert-butyl) 4-methyl 4-((4-methoxybenzyl)thio)piperidine-1,4-dicarboxylate.

[0250] MS (ESI) m / z C 20 H 29 NO5S [M+H] + Calculated value 396 Measured value 396. Step 2. 1-(tert-butoxycarbonyl)-4-((4-methoxybenzyl)thio)piperidine-4-carboxylic acid A mixture of 1-(tert-butyl) 4-methyl 4-((4-methoxybenzyl)thio)piperidine-1,4-dicarboxylate (7.0 g, 17.7 mmol), LiOH (4.24 g, 17.7 mmol), MeOH (17.7 mL), THF (124 mL), and water (35.4 mL) was stirred at 60° C. for 12 h. The organic solvent was removed under reduced pressure, and the resulting mixture was acidified to pH 5 with 2 M HCl, then extracted with EtOAc (2 mL×3). The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 0-100% EtOAc / DCM, then 0-10% MeOH / DCM) to give pure 1-(tert-butoxycarbonyl)-4-((4-methoxybenzyl)thio)piperidine-4-carboxylic acid.

[0251] MS (ESI) m / z C 19 H 28 NO5S [M+H] + Calculated value 382 Measured value 382. Step 3. tert-Butyl (R)-4-((4-hydroxy-1-phenylbutyl)carbamoyl)-4-((4-methoxybenzyl)thio)piperidine-1-carboxylate A solution of 1-(tert-butoxycarbonyl)-4-((4-methoxybenzyl)thio)piperidine-4-carboxylic acid (300 mg, 0.786 mmol) and HATU (359 mg, 0.944 mmol) in ACN (10.0 mL) was stirred at room temperature for 10 min. To the mixture was added (S)-4-amino-4-phenylbutan-1-ol (130 mg, 0.786 mmol) and DIEA (0.412 mL, 2.36 mmol). The reaction was stirred at room temperature for 24 h. The mixture was concentrated and purified by silica gel column chromatography (5% MeOH / DCM) to give tert-butyl (R)-4-((4-hydroxy-1-phenylbutyl)carbamoyl)-4-((4-methoxybenzyl)thio)piperidine-1-carboxylate.

[0252] MS (ESI) m / z C 29 H 41 N2O5S [M+H]+ Calculated 529, Measured 529. Step 4. tert-Butyl (R)-4-((4-methoxybenzyl)thio)-4-((4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate Dess-Martin periodinane (424 mg, 0.999 mmol) was added to a solution of tert-butyl (R)-4-((4-hydroxy-1-phenylbutyl)carbamoyl)-4-((4-methoxybenzyl)thio)piperidine-1-carboxylate (264 mg, 0.499 mmol) in acetonitrile (5.0 mL) and the reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of Celite. The filtrate was concentrated and the crude material was taken up in EtOAc, washed with saturated aqueous NaHCO3 (2x), brine, dried (Na2SO4), filtered and concentrated to give tert-butyl (R)-4-((4-methoxybenzyl)thio)-4-((4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate. The crude material was carried on to the next step without purification.

[0253] MS (ESI) m / z C 29 H 39 N2O5S [M+H] + Calculated 527, Measured 527. Step 5. (5'S,7a'R)-5'-Phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]thiazol]-3'-one (I-22) tert-Butyl (R)-4-((4-methoxybenzyl)thio)-4-((4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate (260 mg, 0.494 mmol), acetonitrile (5.0 mL) and TFA (0.5 mL, 6.49 mmol) were added to a round-bottom flask. The resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated, taken up in EtOAc, washed with saturated aqueous NaHCO3 (2×), brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, 0-10% MeOH / DCM) to give (5′S,7a′R)-5′-phenyltetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]thiazol]-3′-one.

[0254] MS (ESI) m / z C 16 H 21 N2OS [M+H] + Calculated 289, Measured 289. The compounds shown below in Table 8 were prepared using procedures similar to those described above following the synthetic route for intermediate I-22. [Table 9] Intermediate I-23. Preparation of 5-((5'S)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-5'-yl)nicotinonitrile [ka] Tetrakis(triphenylphosphine)palladium(0) (10 mg, 8.7 μmol) was added to a mixture of (5'S,7a'R)-5'-(5-bromopyridin-3-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (30 mg, 0.085 mmol, I-22A) and dicyanozinc (30 mg, 0.26 mmol) in DMF (1 mL) under N2. The mixture was then stirred at 130° C. for 1 h on the MW. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (Boston Green ODS 150×30 mm×5 um, conditions: water (0.1% TFA)-MeCN starting B 3, ending B 33, gradient time (min) 10, 100% B retention time (min) 2, flow rate (mL / min) 25, injection 2) to give 5-((5′S)-3′-oxotetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-5′-yl)nicotinonitrile.

[0255] MS (ESI) m / z C 16 H 19 N4O2[M+H] + Calculated 299, Measured 299. The compounds shown below in Table 9 were prepared using procedures similar to those described above following the synthetic route of intermediate I-23. [Table 10] Intermediate I-24. Preparation of 1-(tert-butyl) 5'-methyl(5'S)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1,5'-dicarboxylate [ka] Step 1. tert-Butyl 4-cyano-4-hydroxypiperidine-1-carboxylate To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (300 g) in DMSO:H2O=5:1 (20 L) was added trimethylsilyl cyanide (209 g) dropwise at 25° C. under nitrogen atmosphere. The solution was stirred at 50° C. under nitrogen atmosphere for 20 h. The reaction mixture was diluted with water (10 L) and then extracted with (1:5) ethyl acetate:MTBE (6 L×2). The combined organic layers were washed with saturated aqueous NaHCO3 (6 L×2), saturated aqueous FeSO4 (6 L×2), and brine (6 L×2), respectively. The organic layers were dried over anhydrous Na2SO4 and then filtered. The filtrate was then concentrated under reduced pressure to give tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate, which was used directly in the next step without further purification.

[0256] Step 2. 4-Hydroxypiperidine-4-carboxylic acid, HCl To a stirred mixture of HCl (97.5 mL) and acetic acid (97.5 mL) was added tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (30 g) at room temperature under N2 atmosphere. The mixture was stirred at 115° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in acetonitrile (3 L) and the precipitated solid was collected by filtration and washed with acetonitrile (3 L) to give 4-hydroxypiperidine-4-carboxylic acid, HCl. The crude product was used directly in the next step without further purification.

[0257] Step 3. 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid Sodium carbonate (1.46 g) and di-tert-butyl dicarbonate (1.95 g) were added to a solution of 4-hydroxypiperidine-4-carboxylic acid (1 g) in THF (10 mL) and H2O (10 mL) at 0-5 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was extracted with EtOAC (2 x 10 mL). The mixture was acidified to pH 4-5 with 1N HCl. The aqueous layer was washed with EtOAC (3 x 10 mL). The combined organic layers were dried (Na2SO4). After filtration, the filtrate was concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid, which was used directly in the next step without further purification.

[0258] Step 4. tert-Butyl (S)-4-hydroxy-4-((1-methoxy-1-oxopent-4-en-2-yl)carbamoyl)piperidine-1-carboxylate To a stirred solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid (10 g) and methyl (2S)-2-aminopent-4-enoate (19 g) in THF (100 mL) was added DIEA (38.4 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (16.35 g) and HOBT (11.52 g) at room temperature under nitrogen and stirred overnight at room temperature. The reaction mixture was washed with 5% aqueous HCl (10 L), 5% aqueous NaHCO3 (10 L), and saturated aqueous sodium chloride (5 L x 2), respectively, and the organics were dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with petroleum ether / ethyl acetate (10:1)] to give tert-butyl 4-hydroxy-4-{[(2S)-1-methoxy-1-oxopent-4-en-2-yl]carbamoyl}piperidine-1-carboxylate.

[0259] Step 5. tert-Butyl (S)-4-hydroxy-4-((1-methoxy-1,5-dioxopentan-2-yl)carbamoyl)piperidine-1-carboxylate To a stirred solution of silver nitrite (0.26 g) and CuCl2 (0.45 g) in t-butanol:CH3NO2 = 15:1 (4 V, 40 mL) was added dropwise bis(benzonitrile), dichloropalladium (1.29 g) and tert-butyl 4-hydroxy-4-{[(2S)-1-methoxy-1-oxopent-4-en-2-yl]carbamoyl}piperidine-1-carboxylate (10 g) dissolved in t-butanol:CH3NO2 = 15:1 (12 V, 120 mL) under oxygen atmosphere at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was purged with air, filtered, and the filter cake was washed with t-butanol:CH3NO2 = 15:1 (2 × 100 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (S)-4-hydroxy-4-((1-methoxy-1,5-dioxopentan-2-yl)carbamoyl)piperidine-1-carboxylate, which was used directly in the next step without further purification.

[0260] Step 6. Methyl (5'S)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate To a stirred solution of tert-butyl 4-hydroxy-4-{[(2S)-1-methoxy-1,5-dioxopentan-2-yl]carbamoyl}piperidine-1-carboxylate (10 g) in MeCN (150 mL) was added dropwise CHSOH (7.74 g) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure to give methyl (5'S)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate, which was used directly in the next step without further purification.

[0261] Step 7. 1-(tert-butyl) 5'-methyl (5'S)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1,5'-dicarboxylate (Int-I-24.1) To a stirred solution of methyl (5'S)-3'-oxo-tetrahydrospiro[piperidine-4,2'-pyrrolo[2,1-b][1,3]oxazole]-5'-carboxylate (500 mg) in THF (19 mL):H2O (1 mL) was added Na2CO3 (400 mg) and di-tert-butyl dicarbonate (900 μL) at room temperature under nitrogen atmosphere and stirred overnight. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure and the crude product was recrystallized from petroleum ether / ethyl acetate (10:1) to give 1-tert-butyl 5-methyl (5′S)-3′-oxo-tetrahydrospiro[piperidine-4,2′-pyrrolo[2,1-b][1,3]oxazole]-1,5′-dicarboxylate.

[0262] MS (ESI) m / z C 17 H 27 N2O6[M+H] + Calculated 355, Measured 355. 1 H NMR (400 MHz, CDCl3): δ 5.66 - 5.50 (m, 1H), 4.56 (dd, J = 8.5, 5.7 Hz, 1H), 4.06 - 3.86 (m, 2H), 3.75 (d, J = 8.2 Hz, 3H), 3.27 - 3.03 (m, 2H), 2.40 (dtd, J = 13.7, 8.7, 5.1 Hz, 1H), 2.29 - 2.19 (m, 1H), 2.19 - 2.04 (m, 1H), 2.03 - 1.50 (m, 5H), 1.45 (s, 9H). Chiral SFC. 1-(tert-butyl) 5'-methyl (5'S,7a'R)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1,5'-dicarboxylate (I-24) The diastereomeric mixture of 1-(tert-butyl) 5'-methyl (5'S)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1,5'-dicarboxylate (4 g, 11.29 mmol) was subjected to chiral SFC purification (column and dimensions: Lux-4, 21 x 250 mm, 5 um; UV wavelength: 215 nm; flow rate: 80 mL / min; modifier: 10% MeOH (containing 0.1% NH4OH); instrument: Sepiate C2). Peak 1 was collected and concentrated to give 1-(tert-butyl) 5'-methyl (5'S,7a'R)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1,5'-dicarboxylate (2.7 g).

[0263] MS (ESI) m / z C 17 H 27 N2O6[M+H] + Calculated 355, Measured 355. Intermediate I-25. Preparation of (5'S,7a'R)-1-benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylic acid [ka] Step 1. Methyl (5'S,7a'R)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate HCl (3.53 mL, 14.1 mmol) (4 M in dioxane) was added to a solution of 1-(tert-butyl) 5'-methyl (5'S,7a'R)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1,5'-dicarboxylate (1 g, 2.82 mmol, I-24) in DCM (28.2 mL) at room temperature, and the resulting mixture was stirred over the weekend. The reaction was quenched with saturated aqueous NaHCO3 (30 mL) and then stirred at room temperature for 15 min. The layers were separated and the pH of the aqueous layer was confirmed to be basic. The aqueous layer was then extracted twice with DCM (30 mL). The aqueous layer was then extracted (3x) with 25% isopropanol in chloroform (30 mL). The organic layer was dried (MgSO4), filtered, and concentrated to give methyl (5'S,7a'R)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate, which was not purified.

[0264] Step 2. Methyl (5'S,7a'R)-1-benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate Methyl (5'S,7a'R)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate (417 mg, 1.64 mmol) was dissolved in DCM (14.3 mL). TEA (686 μL, 4.92 mmol) was added in one portion and the solution was cooled in an ice bath. Benzoyl chloride (0.209 mL, 1.80 mmol) (diluted in DCM (1.5 mL)) was added slowly and the reaction was allowed to warm to 25° C. and stirred for 1 h. Water (20 mL) and DCM (10 mL) were added, the phases were separated and the aqueous phase was extracted twice with DCM (20 mL). The combined organics were dried (MgSO4), filtered and concentrated. The crude residue was purified by ISCO on a RediSep Gold 24 g column [eluting with 0-100% in hexanes (25% EtOH in EtOAc)] to give methyl (5'S,7a'R)-1-benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate.

[0265] MS (ESI) m / z C 19 H 23 N2O5[M+H] + Calculated 359, Measured 359. Step 3. (5'S)-1-Benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylic acid (I-25) NaOH (891 μL, 1.783 mmol) was added to methyl (5'S)-1-benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylate (300 mg, 0.837 mmol) in ethanol (837 μL) and the resulting mixture was stirred at room temperature for 2 h. DCM (8 mL) and 1 M HCl (8 mL) were added and the resulting mixture was stirred at room temperature for 5 min. The layers were then separated and the pH of the aqueous layer was checked to confirm it was acidic. The aqueous layer was then extracted three times with DCM (10 mL). The combined organic layers were dried (MgSO4) and concentrated to give (5'S)-1-benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylic acid.

[0266] MS (ESI) m / z C 18 H 21 N2O5[M+H] + Calculated 345, Measured 345. Intermediate I-26. Preparation of (5'S,7a'R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] A scintillation vial containing (5'S,7a'R)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (40 mg, 0.137 mmol), 4-bromo-7-chloropyrazolo[1,5-a]pyridine (48 mg, 0.206 mmol, I-20B) and CsF (63 mg, 0.412 mmol) was placed in DMSO (1.4 mL) and the resulting mixture was stirred at 120° C. for 16 h. After cooling, the reaction was partitioned with EtOAC (10 mL), water (3 mL) and saturated aqueous NaHCO3 (3 mL). The layers were separated and the aqueous layer was extracted with EtOAC (15 mL×2). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (MeOH / DCM, 0-50%) to give (5'S,7a'R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5'-(5-fluoropyridin-3-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0267] MS (ESI) m / z C 22 H 22 BrFN5O2[M+H] + Calculated value 486, measured values ​​486, 488. The compounds shown below in Table 10 were prepared using procedures similar to those described above following the synthetic route of intermediate I-26. [Table 11] TIFF2024541944000139.tif101168 Preparation of Intermediate I-27. (5'S)-7'-Fluoro-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA [ka] Step 1. tert-Butyl 4-(((1s)-3-fluoro-4-oxo-1-phenylbutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (5S)-(-)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone dichloroacetate (8.0 mg, 0.023 mmol) (prepared as in I-21.1) and N-fluorobenzenesulfonimide (121 mg, 0.384 mmol) in THF (466 μL) and 2-propanol (46.6 μL) were added to a 20 mL vial. The mixture was stirred at room temperature until homogeneous and then cooled to -10 °C. After 5 min, tert-butyl (S)-4-hydroxy-4-((4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate (30 mg, 0.077 mmol) was added (as a mixture in 100 μL of THF) and stirred. The reaction mixture was quenched with 60 μL of Me2S at about 0° C., diluted with diethyl ether, and then saturated aqueous NaHCO3. The organics were extracted with Et2O / EtOAC (5 mL×3), dried (MgSO4), filtered, and concentrated. tert-Butyl 4-(((1s)-3-fluoro-4-oxo-1-phenylbutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate was carried on crude to the next step.

[0268] MS (ESI) m / z C 21 H 29 FN2O5[M+H-Boc] + Calculated 309, Measured 309. Step 2. (5'S)-7'-Fluoro-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA (I-27) tert-Butyl 4-(((1S)-3-fluoro-4-oxo-1-phenylbutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (31 mg, 0.077 mmol) was added to DCM (500 μL) followed by TFA (70 μL). The mixture was capped and heated at 50° C. overnight. The mixture was concentrated to give (5′S)-7′-fluoro-5′-phenyltetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-3′-one, TFA, which was used in the next step without further purification.

[0269] MS (ESI) m / z C 16 H20 FN2O2[M+H] + Calculated 291, Measured 291. Intermediate I-28. Preparation of (5'S,7a'R)-7a'-methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] Step 1. tert-Butyl 4-hydroxy-4-(((1S)-4-hydroxy-1-phenylpentyl)carbamoyl)piperidine-1-carboxylate Methylmagnesium bromide (3.4 M in 2-methylTHF, 1.32 mL, 4.48 mmol) was added to a solution of tert-butyl (S)-4-hydroxy-4-((4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate (350 mg, 0.896 mmol) (prepared as in I-21.1) in THF (8.9 mL) at 0° C. The reaction mixture was stirred for 20 min and quenched with cold saturated aqueous NH4Cl. The mixture was diluted with DCM (20 mL) and allowed to warm to room temperature. The aqueous layer was extracted with DCM (20 mL×2), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / hexanes, 0-100%) with an ELS detector to give tert-butyl 4-hydroxy-4-(((1S)-4-hydroxy-1-phenylpentyl)carbamoyl)piperidine-1-carboxylate.

[0270] MS (ESI) m / z C 22 H 34 N2O5[M+H] + Calculated value, 407 Measured value, 407. Step 2. tert-Butyl (S)-4-hydroxy-4-((4-oxo-1-phenylpentyl)carbamoyl)piperidine-1-carboxylate tert-Butyl 4-hydroxy-4-(((1S)-4-hydroxy-1-phenylpentyl)carbamoyl)piperidine-1-carboxylate (220 mg, 0.541 mmol) and sodium bicarbonate (54.6 mg, 0.649 mmol) in dry DCM (5.4 mL) were added to a flask. The mixture was cooled to 0 °C, Dess-Martin periodinane (275 mg, 0.649 mmol) was added in one portion, the ice bath was removed after 5 min, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM (5 mL), quenched with 10% aqueous Na2S2O3, and stirred vigorously for 10 min. The aqueous layer was extracted with DCM (10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl (S)-4-hydroxy-4-((4-oxo-1-phenylpentyl)carbamoyl)piperidine-1-carboxylate.

[0271] MS (ESI) m / z C 22 H 32 NaN2O5[M+Na] + Calculated value, 427 Measured value, 427. Step 3. tert-Butyl (5'S,7a'R)-7a'-methyl-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate To a crude mixture of tert-butyl (S)-4-hydroxy-4-((4-oxo-1-phenylpentyl)carbamoyl)piperidine-1-carboxylate (214 mg, 0.529 mmol) in toluene / THF 5:1 (5.2 mL) was added tosylic acid (50.3 mg, 0.265 mmol). The mixture was stirred at 60° C. for 2 h and at room temperature overnight. The reaction was partitioned with EtOAc (20 mL) and saturated aqueous NaHCO3. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl (5'S,7a'R)-7a'-methyl-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate.

[0272] MS (ESI) m / z C 18 H 23 N2O4[M+H-(tert-butyl)] +Calculated value, 331 Measured value, 331. Step 4. (5'S,7a'R)-7a'-Methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-28) HCl (4M in dioxane, 408 μL, 1.63 mmol) was added dropwise to a solution of tert-butyl (5'S,7a'R)-7a'-methyl-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (126 mg, 0.326 mmol) in DCM (1.3 mL). The mixture was stirred for 15 min and then concentrated under reduced pressure to give (5'S,7a'R)-7a'-methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-3'-one, HCl.

[0273] MS (ESI) m / z C 17 H 23 N2O2[M+H-(tert-butyl)] + Calculated value, 287 Measured value, 287. Intermediate I-29. Preparation of (S)-4-amino-4-(5-fluoro-6-methylpyridin-3-yl)butan-1-ol [ka] Step 1. 6-Chloro-5-fluoronicotinaldehyde iPrMgCl·LiCl (1.3 M in THF) (70 mL, 91 mmol) was added dropwise to a solution of 5-bromo-2-chloro-3-fluoropyridine (16 g, 76 mmol) in THF (250 mL) at −20 °C. The mixture was stirred at −20 °C for 10 min, and then DMF (77 mL, 997 mmol) was added dropwise to the mixture at −20 °C. The mixture was stirred at −20 °C for 30 min. The mixture was quenched with aqueous NH4Cl (200 mL) and extracted with EtOAc (80 mL × 2), the combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Agela® Silica Flash Column, eluent 12% EtOAc / petroleum ether gradient @40 mL / min) to give 6-chloro-5-fluoronicotinaldehyde.

[0274] 1 H NMR (400 MHz, MeOD-d4) δ 8.32-8.28 (m, 1H), 7.80-7.71 (m, 1H). Step 2. (R,E)-N-((6-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide To a stirred mixture of 6-chloro-5-fluoronicotinaldehyde (8.8 g, 55.2 mmol) in THF (200 mL) was added (R)-2-methylpropane-2-sulfinamide (8.7 g, 71.7 mmol) and tetraisopropoxytitanium (25 mL, 83 mmol) at 20° C., and the mixture was stirred at 20° C. for 12 h. The mixture was added to saturated sodium chloride (200 mL), filtered, and extracted with EtOAc (50 mL×3). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 10% ethyl acetate / petroleum ether gradient @35 mL / min) to give (R,E)-N-((6-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide.

[0275] 1 H NMR (400 MHz, MeOD-d4) δ 8.71 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 1.2 Hz, 1H), 8.20-8.24 (m, 1H), 1.28 (s, 9H). Step 3. (R)-N-((S)-1-(6-chloro-5-fluoropyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide To a stirred solution of (R,E)-N-((6-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (7.0 g, 26.6 mmol), indium(III) trifluoromethanesulfonate (22.5 g, 40.0 mmol), and zinc (3.48 g, 53.3 mmol) in THF (500 mL) was added 3-bromoprop-1-ene (4.60 mL, 53.3 mmol), and the mixture was stirred at 20° C. for 12 h. The mixture was quenched with brine (400 mL) and extracted with ethyl acetate (100 mL×3). The combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent 40% ethyl acetate / petroleum ether gradient @35 mL / min) to give (R)-N-((S)-1-(6-chloro-5-fluoropyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide.

[0276] 1 H NMR (400 MHz, MeOD-d4) δ 8.20 (d, J = 1.6 Hz, 1H), 7.73-7.77 (m, 1H), 5.68-5.82 (m, 1H), 5.03-5.14 (m, 2H), 4.53 (t, J = 7.2 Hz, 1H), 2.75 (td, J = 6.8, 14.0 Hz, 1H), 2.55-2.67 (m, 1H), 1.21 (s, 9H). Step 4. (R)-N-((S)-1-(5-fluoro-6-methylpyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide To a solution of (R)-N-((S)-1-(6-chloro-5-fluoropyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (8.0 g, 26.2 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9.88 g, 39.4 mmol), and K2CO3 (10.9 g, 79 mmol) in dioxane (80 mL) and water (8 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.960 g, 1.312 mmol) under N2. The resulting mixture was stirred at 100 °C for 12 h. Water (100 mL) was added and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 100% ethyl acetate / petroleum ether gradient @35 mL / min) to give (R)-N-((S)-1-(5-fluoro-6-methylpyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide.

[0277] 1 H NMR (400 MHz, MeOD-d4) δ 8.22 (s, 1H), 7.53-7.57 (m, 1H), 5.67-5.81 (m, 1H), 5.02-5.12 (m, 2H), 4.48 (t, J = 7.2 Hz, 1H), 2.67-2.80 (m, 1H), 2.54-2.66 (m, 1H), 2.49 (d, J = 2.8 Hz, 3H), 1.20 (s, 9H) Step 5. (R)-N-((S)-1-(5-fluoro-6-methylpyridin-3-yl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide 9-BBN (151 mL, 76 mmol) (0.5 M in THF) was added dropwise to a solution of (R)-N-((S)-1-(5-fluoro-6-methylpyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (4.3 g, 15.1 mmol) in THF (200 mL) at -20°C. After addition, the reaction was stirred at -20°C and allowed to warm to room temperature over 16 h. The mixture was cooled to 0°C and treated with NaOH (1 M) (60.5 mL, 60.5 mmol), hydrogen peroxide (60.5 mL, 691 mmol) and stirred for 2 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAC (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent 10% MeOH / EA gradient @40 mL / min) to give (R)-N-((S)-1-(5-fluoro-6-methylpyridin-3-yl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide.

[0278] MS (ESI) m / z C 14 H 24 FN2O2S [M+H] + Calculated 303, Measured 303. 1 H NMR (400 MHz, MeOD-d4) δ 8.24 (s, 1H), 7.54-7.58 (m, 1H), 4.42 (t, J = 7.2 Hz, 1H), 3.56 (t, J = 6.4 Hz, 2H), 2.49 (d, J = 2.8 Hz, 3H), 1.96-2.08 (m, 1H), 1.84-1.95 (m, 1H), 1.55-1.67 (m, 1H), 1.38-1.51 (m, 1H), 1.19 (s, 9H). Step 6. (S)-4-Amino-4-(5-fluoro-6-methylpyridin-3-yl)butan-1-ol (I-29) To a mixture of (R)-N-((S)-1-(5-fluoro-6-methylpyridin-3-yl)-4-hydroxybutyl)-2-methylpropane-2-sulfinamide (2.4 g, 7.94 mmol) in MeOH (20 mL) was added HCl / MeOH (4M) (3 mL) and the resulting mixture was stirred for 3 h at 20° C. The reaction was directly concentrated to give (S)-4-amino-4-(5-fluoro-6-methylpyridin-3-yl)butan-1-ol.

[0279] MS (ESI) m / z C 10 H 16 FN2O [M+H] + Calculated 199, Measured 199. 1 H NMR (400 MHz, MeOD-d4) δ 8.39-8.43 (m, 1H), 8.16-8.20 (m, 1H), 7.56-7.60 (m, 1H), 6.84-7.02 (m, 3H), 4.91-5.01 (m, 2H), 4.65-4.71 (m, 1H). Intermediate I-30. Preparation of (5'S)-2-methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] 15:30 Step 1. 1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpiperidine-4-carboxylic acid To a solution of 1-(tert-butyl) 4-methyl 4-hydroxy-2-methylpiperidine-1,4-dicarboxylate (6 g, 22.0 mmol) in THF:water 3:1 (150 mL) was added lithium hydroxide (2.63 g, 110 mmol) and the mixture was stirred at 20° C. for 12 h. Water (200 mL) was added to the mixture and the aqueous phase was extracted with EtOAc (1×150 mL). The aqueous phase was acidified with 2M HCl to pH 4 and extracted with EtOAc (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpiperidine-4-carboxylic acid (5 g, 79% yield).

[0280] Step 2. tert-Butyl 4-hydroxy-4-(((S)-4-hydroxy-1-phenylbutyl)carbamoyl)-2-methylpiperidine-1-carboxylate A flask was charged with 1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpiperidine-4-carboxylic acid (643 mg, 2.48 mmol), (S)-4-amino-4-phenylbutan-1-ol hydrochloride (500 mg, 2.48 mmol), TEA (1.04 mL, 7.44 mmol), EDC (713 mg, 3.72 mmol) and HOBT (569 mg, 3.72 mmol) in DMF (10 mL) and stirred at 25° C. for 16 h to give a yellow mixture. The reaction mixture was added with water (10 mL) and extracted with EtOAC (20 mL×3). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 75% ethyl acetate / petroleum ether gradient @40 mL / min) to give tert-butyl 4-hydroxy-4-(((S)-4-hydroxy-1-phenylbutyl)carbamoyl)-2-methylpiperidine-1-carboxylate (690 mg) as a colorless oil.

[0281] Step 3. tert-Butyl 4-hydroxy-2-methyl-4-(((S)-4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate To a solution of tert-butyl 4-hydroxy-4-(((S)-4-hydroxy-1-phenylbutyl)carbamoyl)-2-methylpiperidine-1-carboxylate (690 mg, 1.70 mmol) in DCM (12 mL) was added DMP (1.08 g, 2.55 mmol) at 0° C. The resulting mixture was stirred at 20° C. for 16 h. Saturated aqueous NaHCO3 (8 mL) was added to the reaction and extracted with DCM (12 mL×2). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-hydroxy-2-methyl-4-(((S)-4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate (670 mg) as a yellow oil, which was used in the next step without further purification.

[0282] Step 4. (5'S)-2-Methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-30) To a solution of tert-butyl 4-hydroxy-2-methyl-4-(((S)-4-oxo-1-phenylbutyl)carbamoyl)piperidine-1-carboxylate (670 mg, 1.66 mmol) in toluene (12 mL) was added p-toluenesulfonic acid monohydrate (315 mg, 1.66 mmol) and the resulting mixture was stirred at 80° C. for 12 h. The precipitate was then filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (Instrument EJ; Method Column Boston Green ODS 150×30 mm×5 um Conditions Water (TFA)-ACN Start B 30 End B 50 Gradient Time (min) 10 100% B Retention time (min) 2 Flow rate (mL / min) 25) to give (5'S)-2-methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0283] MS (ESI) m / z C 17 H 23 N2O2[M+H]+ calculated 287, found 287. 1 H NMR (400 MHz, CDCl3): δ 7.31-7.40 (m, 3H), 7.29 (s, 1H), 7.23 (br d, J = 8.0 Hz, 2H), 5.59-5.73 (m, 1H), 5.06 (t, J = 7.6 Hz, 1H), 3.43 (br d, J = 7.2 Hz, 2H), 3.19-3.37 (m, 3H), 2.59-2.68 (m, 1H), 2.25-2.33 (m, 1H), 2.10 (br d, J = 6.0 Hz, 2H), 1.67-1.86 (m, 2H), 1.33-1.41 (m, 3H). Intermediate I-31. Preparation of (5'S)-2-methyl-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] Step 1. Benzyl 4-cyano-4-((trimethylsilyl)oxy)piperidine-1-carboxylate Benzyl 4-oxopiperidine-1-carboxylate (10.0 g, 42.9 mmol) was charged to a flask and dissolved in CH2Cl2 (21 mL). 18-crown-6 (1.13 g, 4.29 mmol) and KCN (0.279 g, 4.29 mmol) were added at room temperature. The resulting solution was cooled to 0 °C and TMS-CN (6.90 mL, 51.4 mmol) was added dropwise under N2 atmosphere (exothermic process). The ice bath was removed and the reaction was aged at ambient temperature for 5 h. The reaction was quenched with NaHCO3 (aqueous saturated 50 mL). The layers were separated and the aqueous layer was backwashed with CH2Cl2 (15 mL x 2). The combined organic layers were dried (Na2SO4), filtered and concentrated. Benzyl 4-cyano-4-((trimethylsilyl)oxy)piperidine-1-carboxylate was isolated as an oil which was used without further purification.

[0284] Step 2. Benzyl 4-carbamoyl-4-hydroxypiperidine-1-carboxylate Benzyl 4-cyano-4-((trimethylsilyl)oxy)piperidine-1-carboxylate (14.8 g, 42.9 mmol) was dissolved in acetic acid (42.9 mL) and treated sequentially with palladium(II) nitrate dihydrate (343 mg, 1.29 mmol) and acetamide (10.1 g, 171 mmol) under inert atmosphere. The resulting mixture was heated to 50° C. and aged for 13 h. The cake was washed with EtOAc (50 mL) and the solution was concentrated. The residue was partitioned with EtOAC (50 mL) / aqueous NaHCO3 (5 w / w%, 50 mL) and the organics were washed three times with NaHCO3 (5 w / w% aq, 50 mL). The aqueous layer was backwashed with EtOAc (50 mL×2). The combined organic phases were washed with brine (150 mL), dried (Na2SO4) and concentrated to give benzyl 4-carbamoyl-4-hydroxypiperidine-1-carboxylate as a solid, which was used without further purification.

[0285] Step 3. Benzyl 5'-methoxy-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate Benzyl 4-carbamoyl-4-hydroxypiperidine-1-carboxylate (11.9 g, 42.8 mmol) was dissolved in acetonitrile (86 mL) and treated with 2,5-dimethoxytetrahydrofuran (6.93 mL, 53.4 mmol). To the solution was added p-toluenesulfonic acid hydrate (813 mg, 4.28 mmol) and further heated to 35° C. for 14 h. The mixture was quenched with NaHCO3 (5 w / w% aqueous, 10 mL) and concentrated. The resulting oil was partitioned with EtOAC (100 mL) / aqueous NaHCO3 (5 w / w%, 100 mL) and the layers were separated. The aqueous layer was backwashed with EtOAc (30 mL×2). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 75% ethyl acetate / ethanol and hexane gradient) to give benzyl 5'-methoxy-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate as a colorless oil.

[0286] Step 4. Benzyl 3'-oxo-7',7a'-dihydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (I-31) Benzyl 5'-methoxy-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (10.4 g, 28.9 mmol) was dissolved in acetic acid (577 mL) and transferred to a two-necked round-bottom flask equipped with an addition funnel and a distillation head. To the solution, under an inert atmosphere, was added quinoline (2.56 mL, 21.7 mmol) and camphorsulfonic acid (3.35 g, 14.4 mmol). The resulting mixture was refluxed. Acetic acid was slowly added to the solution in place of the distilled amount. This process was continued for 2 hours and the conversion was monitored by NMR of an aliquot. Once complete replacement of the methoxide was achieved, the reaction was stripped of acetic acid and the residue was redissolved in dry toluene (577 mL). Distillation was continued for an additional 4 hours with continuous replenishment of toluene. When >90% conversion was achieved by H NMR, residual solvent was removed and the mixture was redissolved in EtOAc (200 mL). The organic layer was washed with HCl (aqueous 1M, 150 mL x 2), brine (200 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent 75% ethyl acetate / ethanol and hexane gradient) to give benzyl 3'-oxo-7',7a'-dihydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate as a colorless oil. The enantiomers were separated by chiral SFC (column AD-H 21 x 250 mm, 5 μm, UV wavelength = 215 nm, flow rate = 70 mL / min).

[0287] Intermediate I-32. Preparation of ((5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-8-azaspiro[bicyclo[3.2.1]octane-3,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] Step 1. tert-Butyl 3-cyano-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44 mmol) and trimethylsilanecarbonitrile (7.10 mL, 53.3 mmol) in THF (200 mL) under N2, butyllithium (1.06 mL, 2.66 mmol) was added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with water (200 mL), extracted with EtOAc (200 mL x 3), and the organic layer was washed with brine (200 mL x 2), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 5% ethyl acetate / petroleum ether gradient @35 mL / min) to give the product tert-butyl 3-cyano-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (13 g).

[0288] Step 2. Methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-3-carboxylate A solution of tert-butyl-cyano-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.5 g, 20.0 mmol) in HCl·MeOH (4 M, 100 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated to give crude methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-3-carboxylate (3.7 g), which was used directly in the next step.

[0289] Step 3. 8-(tert-butyl) 3-methyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate To a solution of methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-3-carboxylate (3.7 g, 20.0 mmol) in DCM (70 mL) was added di-tert-butyl dicarbonate (5.51 mL, 24.0 mmol) and triethylamine (13.9 mL, 100 mmol) at 20° C., and the resulting mixture was stirred for 2 h at 20° C. The solution was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 10% EtOAc / petroleum ether gradient @45 mL / min) to give 8-(tert-butyl) 3-methyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate.

[0290] Step 4. 8-(tert-butoxycarbonyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-3-carboxylic acid A mixture of 8-(tert-butyl) 3-methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (4.7 g, 16.5 mmol) and LiOH (1.18 g, 49.4 mmol) in THF (40 mL) and HO (14 mL) was stirred at 25 °C for 2 h. The solvent was evaporated and the reaction mixture was then quenched with aqueous 1 M HCl (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 8-(tert-butoxycarbonyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-3-carboxylic acid.

[0291] Step 5. tert-Butyl 3-(((S)-1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of 8-(tert-butoxycarbonyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-3-carboxylic acid (350 mg, 1.29 mmol), N-ethyl-N-isopropylpropan-2-amine (0.676 mL, 3.87 mmol) and HATU (981 mg, 2.58 mmol) in DMF (10 mL) was added (S)-4-amino-4-(3,5-difluorophenyl)butan-1-ol (286 mg, 1.41 mmol) and the resulting mixture was stirred at 20° C. for 12 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (25 mL×3). The organics were dried (Na2SO4), filtered and concentrated. The mixture was purified by HPLC [(instrument ed; Method Column Boston Prime C18 150 mm × 30 mm × 5 um; conditions water (NH3H2O ​​+ NH4HCO3)-CAN; flow rate 25 mL / min)] to give tert-butyl 3-(((S)-1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate.

[0292] MS (ESI) m / z C 23 H 33 F2N2O5[M+H]+ calculated 455, found 455. 1 H NMR (500MHz, CDCl3): δ 6.73-6.79 (m, 2H), 6.68 (tt, J = 8.8, 2.0 Hz, 1H), 4.80-4.91 (m, 1H), 4.28 (br s, 2H), 3.68 (br s, 2H), 2.13-2.25 (m, 2H), 1.86-1.99 (m, 4H), 1.53-1.68 (m, 4H), 1.53-1.69 (m, 1H), 1.49 (s, 9H). Step 6. tert-Butyl 3-(((S)-1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(((S)-1-(3,5-difluorophenyl)-4-hydroxybutyl)carbamoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.880 mmol) and pyridine (71 uL, 0.88 mmol) in DCM (10 mL) was added DMP (747 mg, 1.76 mmol) at 0° C. and the resulting mixture was stirred at 20° C. for 1 h. The reaction was quenched with saturated aqueous Na2SO3 (15 mL) and stirred for 10 min. Saturated aqueous NaHCO3 (15 mL) was added and the mixture was extracted with DCM (10 mL×2). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give tert-butyl 3-(((S)-1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, which was used in the next step without further purification.

[0293] Step 7. (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-8-azaspiro[bicyclo[3.2.1]octane-3,2'-pyrrolo[2,1-b]oxazol]-3'-one To a mixture of tert-butyl 3-(((S)-1-(3,5-difluorophenyl)-4-oxobutyl)carbamoyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.884 mmol) in acetonitrile (6 mL) was added TsOH (0.166 mL, 2.65 mmol) and the resulting mixture was stirred at 80 °C for 2 h. The crude mixture was concentrated and purified by HPLC [(Instrument EK; Method Column Boston Uni C18 40 mm x 150 x 5 um; Conditions water (TFA)-CAN Start B 25 End B 55 Gradient time (min) 10; Flow rate 60 mL / min)] to give (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-8-azaspiro[bicyclo[3.2.1]octane-3,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0294] MS (ESI) m / z C 18 H 21 F2N2O2[M+H]+ calculated 335, found 335. Intermediate I-33. Preparation of 3'-(3,5-difluorophenyl)dihydro-1'H,3'H,5'H-spiro[piperidine-4,6'-pyrrolo[1,2-c]oxazol]-5'-one [ka] Step 1. 1-(tert-butyl) 4-methyl 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)piperidine-1,4-dicarboxylate To a solution of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (4.0 g, 16.4 mmol) in THF (70 mL) was added LDA (12.3 mL, 24.7 mmol) at -78 °C. The mixture was stirred at this temperature for 30 min. Then, a solution of ((2-(bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane (5.23 g, 19.73 mmol) in THF (10 mL) was added at -78 °C. After addition, the mixture was warmed to 20 °C and stirred at 20 °C for 16 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 2), and the organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent 0-20% EtOAc / petroleum ether gradient @25 mL / min) to give 1-(tert-butyl) 4-methyl 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)piperidine-1,4-dicarboxylate (3.5 g) as an oil.

[0295] Step 2. 1-(tert-butyl) 4-methyl 4-(3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)piperidine-1,4-dicarboxylate To a solution of 1-(tert-butyl) 4-methyl 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)piperidine-1,4-dicarboxylate (3.0 g, 7.01 mmol) in dioxane (60 mL) and water (20 mL) was added 2,6-dimethylpyridine (1.50 g, 14.0 mmol) and OsO4 (0.25 g, 0.983 mmol) at 0 °C. The mixture was stirred at this temperature for 10 min. Sodium periodate (6.00 g, 28.1 mmol) was added and the mixture was stirred at 20 °C for 3 h. The mixture was quenched with saturated aqueous Na2SO3 (300 mL), adjusted to pH = 10, and extracted with EtOAC (200 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent 0-10% EtOAc / petroleum ether gradient @30 mL / min) to give 1-(tert-butyl) 4-methyl 4-(3-(((tert-butyldimethylsilyl)oxy)-2-oxopropyl)piperidine-1,4-dicarboxylate (1.6 g) as a brown oil.

[0296] Step 3. tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate To a solution of 1-(tert-butyl) 4-methyl 4-(3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)piperidine-1,4-dicarboxylate (1.5 g, 3.49 mmol) in MeOH (40 mL) was added ammonium formate (2.20 g, 34.9 mmol) and NaCNBH4 (0.549 g, 8.73 mmol). The mixture was sealed and stirred at 40 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 10-60% EtOAc / petroleum ether gradient @25 mL / min) to give tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (750 mg) as a white solid.

[0297] MS (ESI) m / z C 20 H 39 N2O4Si [M+H] + Calculated 399, Measured 399. Step 4. tert-Butyl 3-(hydroxymethyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate To a solution of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (650 mg, 1.63 mmol) in MeOH (10 mL) was added NHF (604 mg, 16.3 mmol). The mixture was stirred at 40 °C for 16 h. The solvent was evaporated under reduced pressure and the crude was diluted with HO (10 mL) and extracted with DCM (20 mL x 3). The combined organics were washed with brine (15 mL), dried (NaSO), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 3-(hydroxymethyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (470 mg, 91% yield) as a white solid, which was used directly in the next step.

[0298] MS (ESI) m / z C 14 H24 N2NaO4[M+Na] + Calculated 307, Measured 307. 1 H NMR (400MHz, CDCl3): δ 6.58 (s, 1H), 4.01 (br s, 2H), 3.68-3.85 (m, 2H), 3.41-3.53 (m, 1H), 2.82-3.08 (m, 3H), 2.19 (br dd, J = 12.8, 7.6 Hz, 1H), 1.87-1.98 (m, 1H), 1.72-1.84 (m, 2H), 1.62 (br dd, J = 12.4, 7.6 Hz, 1H), 1.46 (s, 10H). Step 5. 3'-(3,5-difluorophenyl)dihydro-1'H,3'H,5'H-spiro[piperidine-4,6'-pyrrolo[1,2-c]oxazol]-5'-one To a mixture of tert-butyl 3-(hydroxymethyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.703 mmol) and 3,5-difluorobenzaldehyde (100 mg, 0.703 mmol) in acetonitrile (3 mL) was added MsOH (0.132 mL, 2.11 mmol) and the resulting mixture was stirred at 80 °C for 1 h. This mixture was purified by HPLC (Instrument EE; Method Column YMC-Actus Triart C18 150×30 mm×5 um; Conditions Water (TFA)-CAN Start B 25 End B 45 Gradient Time (min) 10.5; 100% B Retention Time (min) 1.5 Flow (mL / min) 40; Injection 3) to give 3'-(3,5-difluorophenyl)dihydro-1'H,3'H,5'H-spiro[piperidine-4,6'-pyrrolo[1,2-c]oxazol]-5'-one as a yellow oil.

[0299] MS (ESI) m / z C 16 H 19 F2N2O2[M+H] + Calculated 309, Measured 309. Intermediate I-34. Preparation of (5'S,7a'R)-7'-hydroxy-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one [ka] Step 1. tert-Butyl (S)-4-hydroxy-4-((1-phenylbut-3-en-1-yl)carbamoyl)piperidine-1-carboxylate A mixture of (S)-1-phenylbut-3-en-1-amine hydrochloride (2.50 g, 8.15 mmol), 1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-carboxylic acid (2.0 g, 8.15 mmol), HOBT (1.87 g, 12.2 mmol), EDC (2.34 g, 12.2 mmol), and TEA (3.41 mL, 24.5 mmol) in DMF (30 mL) was stirred at 25 °C for 16 h to give a yellow mixture. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent 0-35% ethyl acetate / petroleum ether gradient @60 mL / min) to give tert-butyl (S)-4-hydroxy-4-((1-phenylbut-3-en-1-yl)carbamoyl)piperidine-1-carboxylate.

[0300] MS (ESI) m / z C 21 H 31 N2O4[M+H] + Calculated 375, Measured 375. Step 2. tert-Butyl 4-(((1S)-3,4-dihydroxy-1-phenylbutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate To a solution of tert-butyl (S)-4-hydroxy-4-((1-phenylbut-3-en-1-yl)carbamoyl)piperidine-1-carboxylate (2.7 g, 7.21 mmol) in acetone (21 mL) and water (7 mL) was added NMO (2.11 g, 18.0 mmol), potassium osmate(vi) dihydrate (0.266 g, 0.721 mmol) and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with aqueous Na2S2O3 (40 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent 100% ethyl acetate / petroleum ether gradient @35 mL / min) to give tert-butyl 4-(((1S)-3,4-dihydroxy-1-phenylbutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (1.9 g) as a solid.

[0301] 1 H NMR (500 MHz, CD3OD) δ 7.28-7.38 (m, 4H), 7.19-7.26 (m, 1H), 4.98-5.21 (m, 1H), 3.85-4.01 (m, 2H), 3.39-3.66 (m, 3H), 2.96-3.23 (m, 2H), 2.02-2.06 (m, 1H), 1.76-2.01 (m, 3H), 1.47-1.61 (m, 2H), 1.43-1.47 (m, 9H). Step 3. tert-Butyl (5'S,7a'R)-7'-hydroxy-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate To a solution of tert-butyl 4-(((1S)-3,4-dihydroxy-1-phenylbutyl)carbamoyl)-4-hydroxypiperidine-1-carboxylate (700 mg, 1.71 mmol) and trichloroisocyanuric acid (418 mg, 1.80 mmol) in DCM (15 mL) was added TEMPO (2.68 mg, 0.017 mmol) at 0° C. and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent 40% ethyl acetate / petroleum ether gradient @35 mL / min) to give tert-butyl (5'S,7a'R)-7'-hydroxy-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate as a colorless oil.

[0302] MS (ESI) m / z C 21 H 29 N2O5[M+H] + Calculated 389, Measured 389. Step 4. (5'S,7a'R)-7'-Hydroxy-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one To a mixture of tert-butyl (5'S,7a'R)-7'-hydroxy-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (50 mg, 0.129 mmol) in DCM (2 mL) was added TFA (0.2 mL) and the resulting mixture was stirred for 2 h at 25° C. The reaction was concentrated to give (5'S,7a'R)-7'-hydroxy-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-3'-one, TFA, as a colorless oil, which was used in the next step without further purification.

[0303] MS (ESI) m / z C 16 H 21 N2O3[M+H] + Calculated 289, Measured 289. Working Example Example 1.1 [ka] (5'S,7a'R)-1-Benzoyl-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, hydrochloride salt (I-21) (1.59 g, 4.61 mmol) was added to a 250 mL round bottom flask followed by dry DCM (15.4 mL). The mixture was cooled to 0° C. and triethylamine (1.29 mL, 9.22 mmol) was added in one portion. Benzoyl chloride (563 μL, 4.84 mmol) was added dropwise over 1 min. After 10 min, the mixture was allowed to warm slowly to room temperature over 30 min. The solvent was evaporated and the resulting oil was taken up in EtOAC (50 mL). The organics were washed with saturated aqueous NH4Cl (15 mL), then saturated aqueous NaHCO3 (15 mL), then brine. The organics were dried (MgSO4), filtered, and concentrated. The oil was taken up in isopropanol (10 mL) in a 250 mL flask and heated until completely dissolved. The mixture was stirred at room temperature, cooled for 5 min, and hexanes (50 mL) was added in one portion. The mixture was stirred at room temperature overnight and the resulting precipitate was filtered to give (5'S,7a'R)-1-benzoyl-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0304] MS (ESI) m / z C 23 H 23 F2N2O3[M+H] + Calculated value 413, measured value 413. 1H NMR (499 MHz, DMSO-d6) δ 7.50 - 7.36 (m, 5H), 7.14 (t, J = 9.4 Hz, 1H), 7.07 (d, J = 6.7 Hz, 2H), 5.80 (s, 1H), 4.94 (t, J = 7.8 Hz, 1H), 4.31 (s, 1H), 3.58 (s, 1H), 3.18 (d, J = 5.1 Hz, 2H), 2.64 (s, 1H), 2.19 (dd, J = 7.2, 4.9 Hz, 1H), 1.86 (ddd, J = 19.6, 12.9, 7.2 Hz, 2H), 1.70 (d, J = 43.0 Hz, 3H). The compounds in Table 11 below were prepared from the following intermediates using the methods described in Example 1.1: Intermediates I-21 (Table 7), I-16 (Table 5), I-19, I-20, I-22 (Table 8), I-35, I-38, I-45, and I-46. [Table 12] TIFF2024541944000150.tif231158TIFF2024541944000151.tif234157TIFF2024541944000152.tif102157The compounds in Table 12 below were prepared from the general intermediates in Table 7, I-47 and Table 13 above using the method described in Example 1.1. Example 2.1 was prepared using a slightly modified procedure where the reaction was carried out in THF, DIEA was used as the base, and the reaction was carried out at 20° C. for 12 hours. Examples 2.4 to 2.7 were purified by SFC, and the SFC conditions are listed after the table. [Table 13] TIFF2024541944000154.tif152164 Examples 2.4 / 2.5 / 2.6 / 2.7: (5'S,7a'R)-1-Benzoyl-5'-(3,5-difluorophenyl)-3-methyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one was purified by Chiral-Prep SFC [Column: Lux-4, 21 x 250 mm: 30% [0.1% NHOH in MeOH] / CO2; Flow rate: 70 mL / min; 1st eluting peak (2.4); 2nd eluting peak (2.5); 3rd eluting peak (2.6); 4th eluting peak (2.7)].

[0305] Example 3.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one in DMA (1622 μL), HCl (75 mg, 0.24 mmol) (I-21) and 7-chloro-3-fluoropyrazolo[1,5-a]pyrimidine (42 mg, 0.24 mmol) were added to a flask. Hunig's base (85 μL, 0.49 mmol) was added in one portion and the mixture was heated to 55° C. for 90 min. The solvent was removed and the residue was purified by flash silica gel chromatography (ISCO SiO2 4 g; ethyl acetate in hexanes, 20-70%). The desired fractions were combined and the volatiles were evaporated to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0306] MS (ESI) m / z C 22 H 21 F3N5O2[M+H] + Calculated value 404, measured value 404. 1H NMR (499 MHz, DMSO-d6) δ 8.28 (dd, J = 11.2, 4.2 Hz, 2H), 7.19 - 7.01 (m, 3H), 6.47 (d, J = 5.0 Hz, 1H), 5.93 - 5.77 (m, 1H), 4.96 (t, J = 7.8 Hz, 1H), 4.37 (d, J = 12.7 Hz, 1H), 4.28 (d, J = 12.7 Hz, 1H), 3.49 (t, J = 10.9 Hz, 1H), 2.65 (dq, J = 13.3, 7.7, 6.8 Hz, 1H), 2.20 (d, J = 12.3 Hz, 2H), 2.12 (td, J = 13.7, 4.4 Hz, 1H), 2.02 - 1.84 (m, 2H), 1.81 (t, J = 13.8 Hz, 1H), 1.70 (tt, J = 11.5, 7.6 Hz, 1H). Example 4.1 [ka] (5'S,7a'R)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (I-21C) (13 mg, 0.048 mmol) was added to a vial containing 7-chloro-3-fluoropyrazolo[1,5-a]pyrimidine (8.19 mg, 0.048 mmol) in DMA (477 μL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (26 μL, 0.143 mmol) and the mixture was capped and heated to 75° C. for 60 min. The residue was purified by flash silica gel chromatography (ISCO SiO2 4 g; ethyl acetate in hexanes, 30-70%). The desired fractions were combined and the volatiles were evaporated to give (5'S,7a'R)-1-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0307] MS (ESI) m / z C 22H 23 FN5O2[M+H] + Calculated value 408, measured value 408. 1 H NMR (499 MHz, DMSO-d6) δ 8.29 (dd, J = 12.9, 4.2 Hz, 2H), 7.43 - 7.18 (m, 5H), 6.47 (d, J = 5.1 Hz, 1H), 5.83 (dd, J = 7.1, 5.1 Hz, 1H), 4.94 (t, J = 7.8 Hz, 1H), 4.38 (d, J = 13.0 Hz, 1H), 4.29 (d, J = 12.6 Hz, 1H), 3.49 (t, J = 10.7 Hz, 1H), 3.39 (d, J = 12.2 Hz, 2H), 2.64 (ddd, J = 13.0, 7.8, 5.3 Hz, 1H), 2.22 (dd, J = 7.1, 4.5 Hz, 1H), 2.16 - 2.04 (m, 2H), 2.00 - 1.83 (m, 2H), 1.83 - 1.63 (m, 2H). The compounds in Table 13 below were prepared from general intermediate I-21 or intermediates described in Tables 7, 8 or 9 using the methods described in Example 4.1. [Table 14] TIFF2024541944000158.tif216163TIFF2024541944000159.tif221163TIFF2024541944000160.tif216163TIFF2024541944000161.tif224163TIFF2024541944000162.tif229164TIFF2024541944000163.tif216164TIFF2024541944000164.tif227163TIFF2024541944000165.tif243164TIFF2024541944000166.tif218164TIFF2024541944000167.tif236164TIFF2024541944000168.tif214163TIFF2024541944000169.tif234163TIFF2024541944000170.tif221163TIFF2024541944000171.tif219164TIFF2024541944000172.tif231164TIFF2024541944000173.tif239166TIFF2024541944000174.tif241164TIFF2024541944000175.tif221164TIFF2024541944000176.tif244164TIFF2024541944000177.tif230165TIFF2024541944000178.tif221165TIFF2024541944000179.tif233162TIFF2024541944000180.tif206164TIFF2024541944000181.tif215164TIFF2024541944000182.tif221164TIFF2024541944000183.tif235164TIFF2024541944000184.tif220164TIFF2024541944000185.tif223164TIFF2024541944000186.tif215164TIFF2024541944000187.tif229164TIFF2024541944000188.tif224163TIFF2024541944000189.tif236163TIFF2024541944000190.tif231164TIFF2024541944000191.tif228164TIFF2024541944000192.tif243164TIFF2024541 944000193.tif241164TIFF2024541944000194.tif225164TIFF2024541944000195.tif117164. Example 5.1 [ka] (5'S,7a'R)-1-(2,5-difluorobenzoyl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (12 mg, 0.039 mmol) was added to a vial containing DCM (389 μL) at room temperature. HOBT (7.2 mg, 0.047 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (9.0 mg, 0.047 mmol) were added, followed by 2,5-difluorobenzoic acid (7.38 mg, 0.047 mmol) in one portion. The mixture was stirred at room temperature for 3 h. The mixture was concentrated, loaded onto DMA, and the residue was purified by preparative HPLC reverse phase (C-18) eluting with acetonitrile / water + 0.05% NH3 to give (5'S,7a'R)-1-(2,5-difluorobenzoyl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one as a solid.

[0308] MS (ESI) m / z C 23 H 21 F4N2O3[M+H] + Calculated 449, Measured 449. 1H NMR (499 MHz, DMSO-d6) δ 7.38 (tt, J = 8.6, 4.2 Hz, 3H), 7.18 - 6.99 (m, 3H), 5.79 (ddd, J = 28.3, 7.1, 5.0 Hz, 1H), 5.00 - 4.84 (m, 1H), 4.45 - 4.23 (m, 1H), 3.51 - 3.35 (m, 1H), 3.29 - 3.11 (m, 2H), 2.63 (tdd, J = 10.7, 8.0, 5.3 Hz, 1H), 2.25 - 2.10 (m, 2H), 1.92 - 1.80 (m, 2H), 1.80 - 1.53 (m, 3H). The compounds in Table 14 below were prepared from common intermediate I-21 or the compounds listed in Table 7 using the methods described in Example 5.1. [Table 15] TIFF2024541944000198.tif220161TIFF2024541944000199.tif241162TIFF2024541944000200.t if219161TIFF2024541944000201.tif221162TIFF2024541944000202.tif236161TIFF20245419440 00203.tif213161TIFF2024541944000204.tif234162TIFF2024541944000205.tif237161TIFF202 4541944000206.tif232161TIFF2024541944000207.tif237162TIFF2024541944000208.tif104162 Example 6.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(5-(trifluoromethyl)pyrazine-2-carbonyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one To a mixture of (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, HCl (I-21) (20 mg, 0.058 mmol) and 5-(trifluoromethyl)pyrazine-2-carboxylic acid (12.2 mg, 0.064 mmol) in MeCN (580 μL) was added Hunig's base (30.4 μL, 0.174 mmol) and 1-propanephosphonic anhydride (69.1 μL, 0.116 mmol) sequentially. The reaction was stirred vigorously at room temperature overnight. The reaction was diluted with DMA, filtered, and purified by prep-HPLC using NH4OH as a modifier to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(5-(trifluoromethyl)pyrazine-2-carbonyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0309] MS (ESI) m / z C 22 H 20 F5N4O3[M+H] + Calculated value, 483 Measured value, 483. 1 H NMR (600 MHz, Methanol-d4) δ 9.07 (s, 1H), 9.02 (s, 1H), 6.98 - 6.89 (m, 2H), 6.89 - 6.80 (m, 1H), 5.82 (ddd, J = 29.7, 7.3, 5.0 Hz, 1H), 4.98 (q, J = 8.2 Hz, 1H), 4.59 - 4.49 (m, 1H), 3.93 - 3.82 (m, 1H), 3.61 - 3.54 (m, 0.5H), 3.51 - 3.42 (m, 1H), 3.39 - 3.32 (m, 0.5 H), 2.77 - 2.68 (m, 1H), 2.32 - 2.20 (m, 1.5H), 2.19 - 2.05 (m, 1.5 H), 2.03 - 1.94 (m, 2H), 1.90 - 1.68 (m, 2H) (mixture of rotamers). The compounds in Table 15 below were prepared from common intermediates I-21, I-28 or the compounds listed in Table 7 using the methods described in Example 6.1. [Table 16] TIFF2024541944000211.tif213164TIFF2024541944000212.tif236164TIFF2024541944000213.tif22416 4TIFF2024541944000214.tif233164TIFF2024541944000215.tif223164TIFF2024541944000216.tif23316 4TIFF2024541944000217.tif218166TIFF2024541944000218.tif221164TIFF2024541944000219.tif22816 4TIFF2024541944000220.tif223163TIFF2024541944000221.tif221164TIFF2024541944000222.tif21116 3TIFF2024541944000223.tif233164TIFF2024541944000224.tif234164TIFF2024541944000225.tif22816 4TIFF2024541944000226.tif238164TIFF2024541944000227.tif217165TIFF2024541944000228.tif21716 4TIFF2024541944000229.tif218164TIFF2024541944000230.tif219164TIFF2024541944000231.tif22616 4TIFF2024541944000232.tif218164TIFF2024541944000233.tif224164TIFF2024541944000234.tif68164 Example 7.1 [ka] (5'S,7a'R)-1-(3-fluorobenzoyl)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one A mixture of (5'S,7a'R)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (40 mg, 0.13 mmol), 3-fluorobenzoic acid (23 mg, 0.165 mmol) and triethylamine (96 μL, 0.69 mmol) in DMF (1.5 mL) was treated with HATU (79 mg, 0.207 mmol). The resulting reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was directly purified by reversed-phase HPLC [TFA method]. This gave (5'S,7a'R)-1-(3-fluorobenzoyl)-5'-(4-fluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0310] MS (ESI) m / z C 23 H 23 F2N2O3[M+H] + Calculated value 413, measured value 413. 1 H NMR (400 MHz, MeOD-d4) δ 7.61 - 7.44 (m, 1H), 7.39 - 7.16 (m, 5H), 7.07 (br t, J = 8.4 Hz, 2H), 5.81 (br s, 1H), 5.06 - 4.93 (m, 1H), 4.63 - 4.34 (m, 1H), 3.69 (br s, 1H), 3.46 - 3.36 (m, 2H), 2.69 (br d, J = 12.2 Hz, 1H), 2.40 - 2.22 (m, 1H), 2.17 - 1.54 (m, 6H). The compounds in Table 16 below were prepared from common intermediates I-28, I-20A, I-23B, or I-17 using the methods described in Example 7.1. [Table 17] TIFF2024541944000237.tif210166TIFF2024541944000238.tif190166 Example 8.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(phenylsulfonyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (14 mg, 0.040 mmol) and benzenesulfonyl chloride (8.8 mg, 0.05 mmol) in THF (450 μL) were added to a vial at room temperature. Triethylamine (11 μL, 0.12 mmol) was added in one portion and the mixture was stirred at room temperature overnight. The mixture was concentrated, loaded onto DMA and the residue was purified by preparative HPLC reverse phase (C-18) eluting with acetonitrile / water + 0.05% NH3 to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(phenylsulfonyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0311] MS (ESI) m / z C 22 H 23 F2N2O4S [M+H] + Calculated 449, Measured 449. 1 H NMR (499 MHz, DMSO-d6) δ 7.78-7.73 (m, 3H), 7.69 - 7.66 (m, 2H), 7.13 - 7.02 (m, 1H), 7.03 (t, J = 8 Hz, 2H), 5.67 - 5.64 (m, 1H), 4.86 (t, 1H), 2.59 - 2.56 (m, 3H), 2.48 - 2.47 (m, 2H), 2.10 - 2.07 (m, 2H), 1.93 - 1.89 (m, 1H), 1.81 - 1.52 (m, 4H). The compounds in Table 17 below were prepared from common intermediate I-21 or the compounds listed in Table 7 using the method described in Example 8.1. [Table 18] TIFF2024541944000241.tif63167 Example 9.1 [ka] (5'S,7'S,7a'R)-7'-Fluoro-1-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (5'S)-7'-Fluoro-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (25 mg, 0.086 mmol, I-27) and 7-chloro-3-fluoropyrazolo[1,5-a]pyrimidine I-13 (17.7 mg, 0.103 mmol) in DMA (1076 μL) were added to a vial. TEA (36 μL, 0.26 mmol) was added in one portion and the mixture was capped and heated to 70° C. for 90 min. The reaction mixture was cooled, diluted with MeOH (2 mL) and filtered. The mixture was purified by preparative HPLC reverse phase (C-18) [eluting with acetonitrile / water + 0.05% NH3] to give (5'S,7'S,7a'R)-7'-fluoro-1-(3-fluoropyrazolo[1,5-a]pyrimidin-7-yl)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0312] MS (ESI) m / z C 22 H 22 F2N5O2[M+H] + Calculated 425, Measured 425. 1H NMR (499 MHz, DMSO-d6) δ 8.29 (dd, J = 12.2, 4.2 Hz, 2H), 7.39 (d, J = 4.4 Hz, 4H), 7.30 (dt, J = 8.7, 4.1 Hz, 1H), 6.49 (d, J = 5.0 Hz, 1H), 5.91 (dd, J = 11.8, 4.1 Hz, 1H), 5.21 - 5.08 (m, 2H), 4.38 (d, J = 12.7 Hz, 1H), 4.30 (d, J = 12.8 Hz, 1H), 3.51 (t, J = 10.9 Hz, 1H), 3.40 (t, J = 11.0 Hz, 1H), 3.08 - 2.94 (m, 1H), 2.15 (ddt, J = 23.4, 17.4, 8.4 Hz, 3H), 2.02 - 1.80 (m, 2H). Example 10.1 [ka] Step 1. (5'S,7a'R)-1-(6-chloropyrimidin-4-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (40 mg, 0.13 mmol) was combined with 4,6-dichloropyrimidine (19.3 mg, 0.130 mmol) along with N-ethyl-N-isopropylpropan-2-amine (69.9 μL, 0.389 mmol) in DMA (1297 μL). The mixture was capped and heated to 60° C. for 60 min. The mixture was cooled and the solvent removed to give crude (5'S,7a'R)-1-(6-chloropyrimidin-4-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, which was carried forward without further purification.

[0313] MS (ESI) m / z C 20 H 20 ClF2N4O2[M+H] + Calculated 421, Measured 421. Step 2. (5'S,7a'R)-1-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one A mixture of (5'S)-1-(6-chloropyrimidin-4-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (45 mg, 0.107 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26 mg, 0.107 mmol), XPHOSPd G3 (4.53 mg, 5.35 μmol), and potassium phosphate tribasic (68 mg, 0.32 mmol) was dissolved in dioxane (1141 μL) / water (285 μL). The mixture was degassed under N2 for 5 min, sealed, and stirred at 80 °C for 2 h. The reaction mixture was cooled, diluted with DMA, filtered and purified by preparative HPLC reverse phase (C-18) eluting with acetonitrile / water + 0.1% NH4 to give (5'S,7a'R)-1-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one.

[0314] MS (ESI) m / z C 24 H 23 F4N6O2[M+H] + Calculated 503, Measured 503. 1H NMR (499 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.88 (t, J = 59.1 Hz, 1H), 7.31 (s, 1H), 7.22 - 7.05 (m, 3H), 5.84 (dd, J = 7.0, 5.1 Hz, 1H), 4.94 (t, J = 7.8 Hz, 1H), 3.44 - 3.34 (m, 4H), 2.65 (dq, J = 13.0, 7.6, 6.5 Hz, 1H), 2.27 - 2.17 (m, 1H), 2.10 (d, J = 13.0 Hz, 1H), 1.95 - 1.79 (m, 2H), 1.71 (tq, J = 11.8, 7.5, 6.0 Hz, 3H). The compounds in Table 18 below were prepared from common intermediates I-21C or I-18 using the method described in Example 10.1. [Table 19] Example 11.1 [ka] 5'-(3,5-difluorophenyl)-1-(4-fluoropyridin-2-yl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one To a solution of 5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one (I-18) (40 mg, 0.105 mmol) in toluene (1 mL) was added 2-bromo-4-fluoropyridine (36.9 mg, 0.210 mmol), Pd2(dba)3 (4.8 mg, 5.2 μmol), sodium 2-methylpropan-2-olate (42.3 mg, 0.440 mmol) and (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (BINAP) (3.26 mg, 5.24 μmol) at 20° C. The mixture was stirred at 95° C. under N2 for 30 h. The mixture was filtered and the filtrate was purified by prep-HPLC (Column Boston Prime C18 150 mm x 30 mm x 5 μm; Conditions: water (0.05% NH3 / H2O+10 mM NH4HCO3)-ACN (gradient time 10 min); 100% B retention time (min) 2 flow rate (25 mL / min)) to give 1-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5'-(3,5-difluorophenyl)-6',7'-dihydro-3'H,5'H-spiro[piperidine-4,2'-pyrrolo[1,2-a]imidazol]-3'-one.

[0315] MS (ESI) m / z C 21 H 20 F3N4O [M+H] + Calculated value 401, measured value 401. 1H NMR (400 MHz, methanol-d4) δ 8.08 (dd, J = 6.0, 9.6 Hz, 1H), 6.86-7.00 (m, 3H), 6.62 (dd, J = 2.0, 12.8 Hz, 1H), 6.45 (ddd, J = 2.0, 6.0, 8.4 Hz, 1H), 5.07 (dd, J = 5.2, 8.0 Hz, 1H), 4.22 (br d, J = 13.6 Hz, 2H), 3.48 (ddd, J = 3.2, 11.2, 14.0 Hz, 2H), 2.70-3.05 (m, 3H), 2.29-2.42 (m, 1H), 1.95 (ddd, J = 4.0, 11.2, 13.2 Hz, 2H), 1.63-1.80 (m, 2H). The compounds in Table 18 below were prepared from general intermediate I-20A using the method described in Example 11.1. [Table 20] TIFF2024541944000247.tif222166TIFF2024541944000248.tif230165TIFF2024541944000249.tif221168TIFF2024541944000250.tif175166 Example 12.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxo-N-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxamide m A mixture of (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one hydrochloride I-21 (30 mg, 0.087 mmol) and DIEA (46 μL, 0.261 mmol) in DCM (1 mL) was cooled to 0 °C and treated with isocyanatobenzene (10 mg, 0.261 mmol). The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was directly concentrated under reduced pressure and the residue was purified by reverse phase HPLC [TFA method]. This gave (5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxo-N-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxamide.

[0316] MS (ESI) m / z C 23 H 24 F2N3O3[M+H] + Calculated 428, Measured 428. 1 H NMR (500 MHz, MeOD-d4) δ 7.38 - 7.32 (m, 2H), 7.29 - 7.23 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.85 (tt, J = 9.1, 2.3 Hz, 1H), 5.81 (dd, J = 7.3, 4.9 Hz, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.15 - 4.03 (m, 2H), 3.40 - 3.34 (m, 1H), 3.29 - 3.24 (m, 1H), 2.72 (dtd, J = 13.2, 7.7, 2.4 Hz, 1H), 2.33 - 2.24 (m, 1H), 2.12 - 1.95 (m, 3H), 1.88 (ddd, J = 13.5, 11.7, 4.5 Hz, 1H), 1.82 - 1.69 (m, 2H). Example 13.1 [ka] (5'S,7a'R)-1-([1,2,4]triazolo[1,5-a]pyridin-5-yl)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA A scintillation vial containing (5'S,7a'R)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, HCl (40 mg, 0.130 mmol), 5-chloro-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 0.194 mmol) and CsF (59 mg, 0.389 mmol) was placed in DMSO (1.3 mL) and the resulting mixture was stirred for 16 h at 120° C. After cooling, the reaction mixture was directly filtered and purified by reverse phase HPLC [TFA method]. This gave (5'S,7a'R)-1-([1,2,4]triazolo[1,5-a]pyridin-5-yl)-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt.

[0317] MS (ESI) m / z C 22 H 24 N5O2[M+H] + Calculated 390, Measured 390. 1H NMR (600 MHz, CD3CN) δ 8.70 (s, 1H), 7.89 (t, J = 8.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.79 (dd, J = 7.3, 5.0 Hz, 1H), 4.94 (t, J = 7.9 Hz, 1H), 4.03 (dt, J = 12.1, 4.1 Hz, 1H), 3.98 (dt, J = 12.4, 3.5 Hz, 1H), 3.46 (td, J = 12.1, 2.9 Hz, 1H), 3.37 (td, J = 12.0, 3.0 Hz, 1H), 2.67 (dtd, J = 13.3, 7.7, 2.2 Hz, 1H), 2.28 - 2.20 (m, 2H), 2.17 (d, J = 13.8 Hz, 1H), 2.10 - 2.01 (m, 1H), 2.00 - 1.91 (m, 1H), 1.89 - 1.83 (m, 1H), 1.74 (tt, J = 11.7, 7.6 Hz, 1H). The compounds in Table 20 below were prepared from common intermediates I-16, I-21 or the compounds listed in Tables 5 and 7 above using the methods described in Example 13.1. [Table 21] TIFF2024541944000254.tif237166TIFF2024541944000255.tif229166TIFF2024541944000256.tif93165 Example 14.1 [ka] 7-((5'S,7a'R)-5'-(3,5-difluorophenyl)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-1-yl)pyrazolo[1,5-a]pyridine-4-carbonitrile, TFA A 2 mL Biotage® microwave vial equipped with a stir bar was charged with (5'S,7a'R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one I-26D (25 mg, 0.050 mmol), Xphos 2nd generation Pd precatalyst (3.9 mg, 0.005 mmol), Zn(CN)2 (8.8 mg, 0.075 mmol) and K3PO4 (15.8 mg, 0.075 mmol). The vial was evacuated and back-filled with nitrogen (3x). A sample of MeCN (0.5 mL) was purged with argon for 15 min with sonication and then added to the reaction vial. The resulting suspension was then stirred at 50° C. for 16 h. After cooling, the reaction was quenched with 1M NaOH (3 mL) and DCM (3 mL). The layers were separated and the aqueous layer was extracted with DCM (3 mL×3). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was taken up in DMSO (2 mL), filtered, and purified by reverse phase HPLC [TFA method]. This gave 7-((5′S,7a′R)-5′-(3,5-difluorophenyl)-3′-oxotetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-1-yl)pyrazolo[1,5-a]pyridine-4-carbonitrile, TFA salt.

[0318] MS (ESI) m / z C 24 H 22 F2N5O2[M+1] + Calculated 450, Measured 450. 1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.09 (d, J = 6.5 Hz, 2H), 6.75 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 5.84 (dd, J = 7.2, 5.0 Hz, 1H), 4.96 (t, J = 7.8 Hz, 1H), 4.21 (d, J = 12.6 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 3.41 (t, J = 10.6 Hz, 1H), 3.32 - 3.25 (m, 1H), 2.70 - 2.60 (m, 1H), 2.24 - 2.11 (m, 3H), 2.02 - 1.94 (m, 1H), 1.88 (ddd, J = 19.8, 12.4, 7.1 Hz, 1H), 1.81 (d, J = 13.5 Hz, 1H), 1.74 - 1.64 (m, 1H). The compounds in Table 21 below were prepared from the general intermediates listed in Table 10 using the method described in Example 14.1. Example 14.3 was prepared using a modified procedure in which the reaction was stirred at 70° C. for 3 days. [Table 22] Example 15.1, Example 15.2 [ka] (5'S,7a'R)-1-(4-chloropyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA (Ex.15.1), and (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(pyrazolo[1,5-a]pyridin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA (Ex.15.2). A 2 mL Biotage® microwave vial equipped with a stir bar was charged with (5'S,7a'R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one I-26d (20 mg, 0.040 mmol), CuCl (11.8 mg, 0.119 mmol) and NMP (0.5 mL). The reaction mixture was then stirred under microwave irradiation at 150° C. for 90 min. The reaction was quenched with water (3 mL) and DCM (3 mL). The layers were separated and the aqueous layer was extracted (3 mL×2). The combined organic layers were dried (MgSO4), filtered through Celite® and concentrated under reduced pressure. The crude residue was taken up in DMSO (2 mL), filtered and purified by reverse phase HPLC [TFA method] to give (5'S,7a'R)-1-(4-chloropyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt and (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(pyrazolo[1,5-a]pyridin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt.

[0319] Example 15.1: MS (ESI) m / z C 23 H 22 ClF2N4O2[M+1] + Calculated 459, Measured 459. 1H NMR (600 MHz, DMSO-d6) δ 8.12 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 7.09 (d, J = 6.6 Hz, 2H), 6.69 (d, J = 2.2 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 5.83 (dd, J = 7.0, 5.2 Hz, 1H), 4.96 (app t, J = 7.8 Hz, 1H), 3.89 (d, J = 11.5 Hz, 1H), 3.81 (d, J = 11.6 Hz, 1H), 3.19 (app, J = 10.2 Hz, 1H), 3.07 (app t, J = 10.5 Hz, 1H), 2.67 - 2.59 (m, 1H), 2.23 - 2.11 (m, 3H), 2.01 - 1.93 (m, 1H), 1.87 (td, J = 13.2, 12.6, 6.6 Hz, 1H), 1.79 (d, J = 12.9 Hz, 1H), 1.73 - 1.64 (m, 1H). Example 15.2: MS (ESI) m / z C 23 H 23 F2N4O2[M+1] + The calculated value is 425, and the measured value is 425. 1H NMR (600 MHz, DMSO-d6) δ 8.01 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.19 - 7.16 (m, 1H), 7.16 - 7.11 (m, 1H), 7.09 (d, J = 6.7 Hz, 2H), 6.60 (d, J = 2.2 Hz, 1H), 6.36 (d, J = 6.8 Hz, 1H), 5.83 (dd, J = 7.1, 5.1 Hz, 1H), 4.96 (t, J = 7.6 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.86 - 3.79 (m, 1H), 3.20 - 3.13 (m, 1H), 3.07 - 3.01 (m, 1H), 2.68 - 2.61 (m, 1H), 2.25 - 2.13 (m, 3H), 2.01 - 1.95 (m, 1H), 1.91 - 1.84 (m, 1H), 1.79 (d, J = 15.4 Hz, 1H), 1.74 - 1.64 (m, 1H). The compounds in Table 22 below were prepared from the common intermediates listed in Table 10 using the methods described in Example 15.1. [Table 23] Example 16.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(4-fluoropyrazolo[1,5-a]pyridin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt A 2 mL Biotage® microwave vial equipped with a stir bar was charged with (5'S,7a'R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one I-26d (10 mg, 0.020 mmol) and Alphos Pd complex (2.3 mg, 0.001 mmol). The vial was then placed in a glove box and KF (0.6 mg, 0.010 mmol) and silver(I) fluoride (5 mg, 0.040 mmol) were added to the vial. Toluene (0.3 mL) was then added and the reaction vial was sealed, removed from the glove box and stirred at 110° C. for 16 h. After cooling, the reaction was partitioned between DCM (3 mL), saturated aqueous NaHCO3 (2 mL) and water (2 mL) and then extracted with DCM (4 mL x 2). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was taken up in DMSO (2 mL), filtered and purified by reverse phase HPLC [TFA method]. This gave (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(4-fluoropyrazolo[1,5-a]pyridin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt.

[0320] MS (ESI) m / z C 23 H 22 F3N4O2[M+1] + Calculated 443, Measured 443. 11H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 2.2 Hz, 1H), 7.18 - 7.05 (m, 4H), 6.77 (d, J = 2.2 Hz, 1H), 6.31 (dd, J = 8.2, 4.5 Hz, 1H), 5.83 (dd, J = 7.0, 5.1 Hz, 1H), 4.96 (app t, J = 7.8 Hz, 2H), 3.80 (d, J = 11.5 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.17 - 3.10 (m, 1H), 3.05 - 2.98 (m, 1H), 2.68 - 2.60 (m, 1H), 2.23 - 2.12 (m, 3H), 2.01 - 1.94 (m, 1H), 1.87 (dt, J = 13.4, 6.6 Hz, 1H), 1.79 (d, J = 12.4 Hz, 1H), 1.72 - 1.63 (m, 1H). Example 17.1 [Chemical formula] (5'S,7a'R)-1-benzoyl-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA A scintillation vial was charged with (5'S,7a'R)-1-benzoyl-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-5'-carboxylic acid I-25 (15 mg, 0.044 mmol), 2-bromopyrazine (10.4 mg, 0.065 mmol), phthalimide (6.4 mg, 0.044 mmol), [Ni(dtbbpy)(HO)]Cl (3.5 mg, 0.009 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) (14.9 mg, 0.087 mmol), and {Ir[dF(CF)ppy](dtbpy)}PF (1.0 mg, 0.009 mmol). The vial was evacuated and back-filled with nitrogen (3x), DMSO (1.1 mL) was added, and the reaction mixture was purged with argon for 15 min. The reaction was then irradiated with 450 nm LED light in a PennOC / Merck photoreactor (stirring 500 rpm, fan speed 1000 rpm, LED power 100%) for 14 h at 25 °C. The reaction mixture was directly filtered and purified by reverse phase HPLC [TFA method]. This gave (5'S,7a'R)-1-benzoyl-5'-(pyrazin-2-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt.

[0321] MS (ESI) m / z C 21 H 23 N4O3[M+1] + Calculated 379, Measured 379. 1H NMR (600 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 7.48 - 7.38 (m, 5H), 5.84 - 5.71 (m, 1H), 5.06 (app t, J = 7.6 Hz, 1H), 4.42 - 4.19 (m, 2H), 3.68 - 3.43 (m, 2H), 3.26 - 3.16 (m, 1H), 2.64 - 2.44 (m, 2H), 2.30 - 2.22 (m, 1H), 2.15 - 2.04 (m, 1H), 1.98 - 1.83 (m, 1H), 1.80 - 1.65 (m, 2H). The compounds in Table 23 below were prepared from general intermediate I-25 using the method described in Example 17.1. [Table 24] TIFF2024541944000264.tif226168TIFF2024541944000265.tif112167 Example 18.1 [ka] (5'S,7a'R)-1-(4-cyclobutylpyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt A 2 mL Biotage® microwave vial equipped with a stir bar was charged with (5′S,7a′R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5′-(3,5-difluorophenyl)tetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-3′-one I-26d (10 mg, 0.020 mmol), NiI (3.1 mg, 0.010 mmol), pyridine-2,6-bis(carboximidamide), 2HCl (2.3 mg, 0.010 μmol), activated Zn powder (6.5 mg, 0.099 mmol) and bromocyclobutane (5.4 mg, 0.040 mmol). The vial was evacuated and back-filled with nitrogen (3x), DMA (0.25 mL) was added and the reaction was stirred at 70°C for 16 h. After cooling, the reaction was partitioned between DCM (3 mL) and water (3 mL) then extracted with DCM (5 mL x 2). The combined organic layers were dried (MgSO4), filtered through Celite® and concentrated under reduced pressure. The crude residue was taken up in DMSO (2 mL), filtered and purified by reverse phase HPLC [TFA method]. This gave (5'S,7a'R)-1-(4-cyclobutylpyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA salt.

[0322] MS (ESI) m / z C 27 H 29 F2N4O2[M+1] + Calculated 479, Measured 479. 1H NMR (600 MHz, DMSO-d6) δ 7.98 (d, J = 2.1 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 7.09 (d, J = 6.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 5.85 - 5.79 (m, 1H), 4.96 (app t, J = 7.9 Hz, 2H), 3.84 (d, J = 12.3 Hz, 1H), 3.75 (d, J = 11.9 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.13 (app t, J = 10.2 Hz, 1H), 3.00 (app t, J = 10.4 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.43 - 2.34 (m, 2H), 2.24 - 2.10 (m, 5H), 2.10 - 2.00 (m, 1H), 2.00 - 1.94 (m, 1H), 1.92 - 1.83 (m, 2H), 1.78 (d, J = 14.1 Hz, 1H), 1.68 (ddd, J = 18.9, 11.6, 7.6 Hz, 1H). The compounds in Table 24 below were prepared from the intermediates listed in Table 10 using the methods described in Example 18.1. [Table 25] Example 19.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA A 2 mL microwave vial equipped with a stir bar was charged with (5'S,7a'R)-1-(4-bromopyrazolo[1,5-a]pyridin-7-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (10 mg, 0.020 mmol), t-BuBrettPhos (0.2 mg, 0.0004 mmol) and NaOt-Bu (2.7 mg, 0.03 mmol). The vial was evacuated and back-filled with nitrogen (3x), MeOH (4.0 μL, 0.099 mmol) was added and the vial was again evacuated and back-filled with N2 (3x). A sample of dioxane (0.3 mL) was purged with argon for 15 min with sonication and then added to a vial containing 3rd generation t-BuBrettPhos Pd precatalyst (0.3 mg, 0.004 mmol) under N2. This solution of precatalyst was stirred at 25 °C for 1 min and then added to the reaction vial. The reaction mixture was then stirred at 70 °C for 3 days. After cooling, the reaction was partitioned between DCM (3 mL) and water (3 mL) and then extracted with DCM (5 mL x 2). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was taken up in DMSO (2 mL), filtered, and purified by reverse phase HPLC [TFA method]. This gave (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one, TFA.

[0323] MS (ESI) m / z C 24 H 25 F2N4O3[M+1] + Calculated 455, Measured 455. 1H NMR (600 MHz, DMSO-d6) δ 7.96 (d, J = 2.2 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.11 - 7.06 (m, 2H), 6.62 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 5.82 (dd, J = 7.1, 5.0 Hz, 1H), 4.95 (app t, J = 7.8 Hz, 1H), 3.88 (s, 3H), 3.74 - 3.68 (m, 1H), 3.66 - 3.60 (m, 1H), 3.07 (app t, J = 10.1 Hz, 1H), 2.99 - 2.91 (m, 1H), 2.64 (ddd, J = 13.0, 7.7, 5.2 Hz, 1H), 2.23 - 2.11 (m, 3H), 2.00 - 1.93 (m, 1H), 1.87 (td, J = 14.4, 13.5, 5.6 Hz, 1H), 1.77 (d, J = 11.4 Hz, 1H), 1.68 (tt, J = 11.6, 7.6 Hz, 1H). The compounds in Table 25 below were prepared from the intermediates listed in Table 10 using the method described in Example 19.1. Examples 19.3, 19.4 and 19.5 were prepared using a modified procedure in which the reaction was stirred at 100° C. for 1.5 days. [Table 26] Example 20.1 [ka] 5-((5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile Step 1. Benzyl (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxo-5',7a'-dihydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate A reaction vessel was sequentially charged with benzyl (R)-3'-oxo-7',7a'-dihydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (150 mg, 0.457 mmol, I-31), 4-iodo-1-methyl-1H-pyrazole (143 mg, 0.685 mmol), tetrabutylammonium chloride (381 mg, 1.37 mmol), potassium acetate (403 mg, 4.11 mmol), and palladium(II) acetate (10.3 mg, 0.046 mmol). The vessel was capped and purged with nitrogen three times. Dry DMF (1.5 mL) was added and the mixture was stirred at 120° C. in a sealed vessel for 16 h. After completion of the reaction, the crude material was directly purified by reversed-phase flash chromatography using C18 modified silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 10-75% acetonitrile / water gradient). Benzyl (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxo-5',7a'-dihydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (143 mg, 0.350 mmol) was isolated as a yellow oil.

[0324] MS (ESI) m / z C 22 H 25 N4O4[M+H] + Calculated 409, Measured 409. Step 2. (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one To a solution of benzyl (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxo-5',7a'-dihydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazole]-1-carboxylate (143 mg, 0.350 mmol) in anhydrous methanol (3.5 mL) was added 10 w / w% palladium on carbon (37.3 mg, 0.035 mmol). The resulting suspension was aged at 22° C. for 17 h under 1 atm of hydrogen. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated. The resulting crude (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one was used without further purification.

[0325] MS (ESI) m / z C 14 H 21 N4O2[M+H] + Calculated 277, Measured 277. Step 3. 5-((5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)-3'-oxotetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile (20.1) (5'S,7a'R)-5'-(1-methyl-1H-pyrazol-4-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (4.0 mg, 0.014 mmol) and 5-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile (3.9 mg, 0.022 mmol) were dissolved in dry DMA (0.3 mL). The resulting solution was treated with diisopropylethylamine (5.61 mg, 0.043 mmol) under an inert atmosphere. The reaction was heated to 60° C. for 2 hours, then cooled and diluted with DMA. The mixture was purified by reverse phase HPLC (C18, 150×30 mm×5 um; water (TFA)-CAN 25-100 gradient; flow rate (mL / min) 40) to give 5-((5′S,7a′R)-5′-(1-methyl-1H-pyrazol-4-yl)-3′-oxotetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile as a solid.

[0326] 1 H NMR (400MHz, DMSO): δ 8.61 (s, 1H), 8.18 (d, J = 4.0 Hz, 1H), 7.64 (s 1H), 7.38 (s, 1H), 6.72 (d, J = 4.0 Hz, 1H), 4.89 - 4.86 (m, 1H), 4.31 - 4.21 (m, 2H), 3.80 (s, 3H), 3.52 - 3.38 (m, 2H), 2.44 (br s, 1H), 2.20 - 1.68 (m, 7H). The compounds in Table 26 below were prepared using intermediate I-31 using the methods and sequences described in Example 20.1. [Table 27] TIFF2024541944000272.tif30164 Example 21.1 [ka] (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(8-(oxazol-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one To a vial was added (5'S,7a'R)-1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (20 mg, 0.040 mmol), Pd(Ph3P)4 (4.58 mg, 3.97 mmol) in DMF (500 uL). 2-(Tributylstannyl)oxazole (18.2 µl, 0.059 mmol) was added in one portion and the mixture was purged with N2 for 5 min, then heated to 100 °C for 1 h. The mixture was cooled and Pd scavenger polymer was added and stirred at room temperature for 15 min. The mixture was diluted with DMF, MeOH and filtered. The residue was purified by preparative HPLC reverse phase (C-18) [eluting with acetonitrile / water + 0.05% NH3] to give (5'S,7a'R)-5'-(3,5-difluorophenyl)-1-(8-(oxazol-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one as a colorless solid.

[0327] MS (ESI) m / z C 25 H 23 F2N6O3[M+H] + Calculated 493, Measured 493. The compounds in Table 27 below were prepared from the intermediates listed in Table 10 using the methods described in Example 21.1. [Table 28] TIFF2024541944000275.tif237170TIFF2024541944000276.tif233170TIFF2024541944000277.tif37170 Example 22.1 [ka] (5'S,7a'R)-1-(2,2-difluoro-1-phenylethyl)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one To a solution of 2,2-difluoro-1-phenylethan-1-one (50.6 mg, 0.324 mmol) and (5'S,7a'R)-5'-(3,5-difluorophenyl)tetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-3'-one (50 mg, 0.162 mmol) in DMSO (1 mL) was added titanium(IV) chloride (6.15 mg, 0.032 mmol), followed by dropwise addition of TEA (0.068 mL, 0.486 mmol). The mixture was stirred at 25°C for 12 h, then NaBH3CN (40.8 mg, 0.649 mmol) in 1 mL of MeOH was added. The mixture was stirred at 25°C for an additional 2 h. The reaction mixture was quenched by adding 5 mL of 1N HCl at 0° C., and then extracted with DCM (15 mL×3). The combined organic layers were dried (Na2SO4), filtered, concentrated under reduced pressure, and purified by Pre-HPLC (EJ Column) [eluted with acetonitrile / water+0.05% NH3] to give (5′S,7a′R)-1-(2,2-difluoro-1-phenylethyl)-5′-(3,5-difluorophenyl)tetrahydro-3′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]oxazol]-3′-one as a solid.

[0328] MS (ESI) m / z C 24 H 25 F4N2O2[M+H] + Calculated 449, Measured 449. 1 H NMR (500 MHz, methanol-d4) δ 7.54 (s, 5H), 6.90-6.96 (m, 2H), 6.82-6.89 (m, 1H), 5.69-5.79 (m, 1H), 4.97 (dt, J=3.43, 7.97 Hz, 2H), 4.64 (br s, 1H), 3.46-3.64 (m, 1H), 2.93-3.27 (m, 3H), 2.67-2.76 (m, 1H), 2.20-2.39 (m, 3H), 1.83-2.15 (m, 3H), 1.67-1.78 (m, 1H). The two diastereomers were further separated on a chiral SFC column [DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 um); 0.1% NH3H2O ​​in IPA, 40-100% IPA; 80 mL / min] to give two compounds.

[0329] The compounds in Table 28 below were prepared from the intermediates using the methods described in Example 22.1. Examples 22.3-22.8 were prepared using the same conditions, except that DCE was used as the solvent and no Lewis acid, TiCl4 was used. [Table 29] Example 23.1 [ka] 5-((5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide A vial was charged with 5-((5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile (40 mg, 0.097 mmol) and KCO (40.0 mg, 0.290 mmol) followed by HO (42.2 µL, 0.483 mmol) in DMSO (965 µL). The mixture was stirred at RT and left overnight. The mixture was diluted with DMA (2 mL), filtered and the residue was directly purified by preparative HPLC reverse phase (C-18) eluted with acetonitrile / water + 0.05% NH3 to give, after drying, 5-((5'S,7a'R)-3'-oxo-5'-phenyltetrahydro-3'H-spiro[piperidine-4,2'-pyrrolo[2,1-b]oxazol]-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide as a colorless solid.

[0330] MS (ESI) m / z C 23 H 25 N6O3[M+H] + Calculated 433, Measured 433.1 H NMR (499 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.64 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.33 (ddd, J = 25.8, 16.6, 7.2 Hz, 4H), 6.80 (d, J = 8.2 Hz, 1H), 5.84 (t, J = 5.6 Hz, 1H), 4.95 (t, J = 7.7 Hz, 1H), 4.20 (d, J = 12.7 Hz, 1H), 4.12 (d, J = 12.2 Hz, 1H), 3.45 (d, J = 11.4 Hz, 1H), 3.31 (s, 2H), 2.24 - 2.16 (m, 2H), 2.15 (s, 1H), 1.98 (t, J = 10.6 Hz, 1H), 1.89 (dd, J = 11.9, 5.8 Hz, 1H), 1.82 (d, J = 14.1 Hz, 1H), 1.75 - 1.68 (m, 1H). Assay RIPK1-ADP-Glo ​​enzyme assay The enzymatic activity of RIPK1 is measured using an assay derived from the ADP-Glo ​​kit (TMPromega), which provides a luminescence-based ADP detection system. Specifically, ADP generated by the RIPK1 kinase is proportionally detected as a homogenous luminescence signal. In this context, the evaluation of the inhibitory effect (EC50) of small molecules is measured by the efficacy of the compound to inhibit the conversion of ATP to ADP by RIPK1.

[0331] In this assay, the potency (EC50) of each compound was determined from a 10-point (1:3 serial dilution; highest compound concentration 100000 nM) titration curve as follows: The assay lower limit or confidence limit is approximately 25 nM. 30 nL of compound (1% DMSO, 3 μL final assay volume) was dispensed into each well of a white ProxiPlus 384-well plate, followed by the addition of 2 μL of 1× 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) enzyme produced from baculovirus-transfected Sf21 cells: MW = 62 kDa). Plates were placed in a humidified chamber at ambient temperature and pre-incubated with compounds for 30 min. Each reaction was then initiated by adding 1 μL of 1× assay buffer containing 900 μM ATP and 3 μM dephosphorylated-MBP substrate. The final reaction of 3 μL per well consisted of 25 nM GST-RIPK1, 300 μM ATP and 3 μM dephosphorylated-MBP. Kinase reactions were allowed to proceed for 150 min before adding ADP-Glo ​​reagent according to the kit protocol outlined by Promega. Dose-response curves were generated by plotting percent effect (% product conversion; Y-axis) versus Log10 compound concentration (X-axis). EC50 values ​​were calculated using a nonlinear regression, four-parameter sigmoidal dose-response model. [Table 30] TIFF2024541944000282.tif245136TIFF2024541944000283.tif245136TIFF2024541944000284.tif245138TIFF2024541944000285.tif244132TIFF2024541944000286.tif245135TIFF2024541944000287.tif244136TIFF2024541944000288.tif245139TIFF2024541944000289.tif244138TIFF2024541944000290.tif243139TIFF2024541944000291.tif244137TIFF2024541944000292.tif244138TIFF2024541944000293.tif245135TIFF2024541944000294.tif245141TIFF2024541944000295.tif244137TIFF2024541944000296.tif244137TIFF2024541944000297.tif244138TIFF2024541944000298.tif242138

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, A is aryl, heteroaryl, heterocycloalkyl or C ３ -C ６ is cycloalkyl; R １ Each occurrence of is -OH, C １ -C ６ AlkylOH, —CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, halogen, -NH ２ , -N(C １ -C ６ alkyl) ２ , —NH(C １ -C ６ alkyl) and C １ -C ６ independently selected from the group consisting of alkoxy; W is CH ２ , N, O or S; X is C(R ４ ) ２ , N, O, or S, where if X is N, there is a dashed line connecting X; ４ ) ２ , O or S, then there is no dashed line connecting X; where X is C(R ４ ) ２ when X is N, O or S, Y is CH ２ and Y is CH ２ , N, O, or S, where when Y is N, there is a dashed line connecting Y; where Y is CH ２ , O, or S, there is no dashed line connecting to Y; and when Y is N, O, or S, X is C(R ４ ) ２ and R ２ is hydrogen, -OH, C １ -C ６ Alkyl OH, CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, halogen, -NH ２ , -N(C １ -C ６ alkyl) ２ , —NH(C １ -C ６ alkyl) or C １ -C ６ alkoxy, or when X or Y is N, R ２ does not exist; R ３ is hydrogen, -OH, C １ -C ６ AlkylOH, —CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, halogen, -NH ２ , -N(C １ -C ６ alkyl) ２ , —NH(C １ -C ６ alkyl) or C １ -C ６ is alkoxy; R ４ Each occurrence of is hydrogen, —OH, C １ -C ６ AlkylOH, —CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, halogen, -NH ２ , -N(C １ -C ６ alkyl) ２ , —NH(C １ -C ６ alkyl) and C １ -C ６ independently selected from the group consisting of alkoxy; Z is —CN, aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl, —SO ２ Heterocycloalkyl, —COOC １ -C ６ Alkyl or -COOC ３ -C ６ cycloalkyl, wherein the aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO ２ Heterocycloalkyl is unsubstituted or substituted with halogen, —CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, C １ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -COOC １ -C ６ Alkyl, -SC １ -C ６ Alkyl, oxo, C ３ -C ６ substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkynyl and C １ -C ６ The alkoxy may be unsubstituted or substituted with halogen, —CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, —OH, and heterocycloalkyl; m is 0, 1, 2 or 3; n is 1 or 2; and p is 1 or 2. or a pharmaceutically acceptable salt thereof.

2. A is aryl, C ３ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl or heteroaryl.

3. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A is aryl, wherein said aryl is phenyl.

4. A is heteroaryl, wherein the heteroaryl is 【Chemistry 2】 【change】 3. The compound of claim 2, wherein:

5. A is C ３ -C ６ cycloalkyl, wherein the C ３ -C ６ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is cyclohexyl or cyclopentyl.

6. R １ Each occurrence of is a halogen, —CN, C １ -C ６ Alkoxy and C １ -C ６ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently selected from the group consisting of alkyl.

7. R １ is independently selected from the group consisting of -CN, fluorine, methoxy and methyl, and m is 1 or 2, or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n and p are both 2.

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n and p are both 1.

10. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

11. W is CH ２ and Y is O and X is CH ２ 2. The compound of claim 1, wherein:

12. W is CH ２ and Y is S and X is CH ２ 2. The compound of claim 1, wherein:

13. W is CH ２ and Y is CH ２ and X is O, or a pharmaceutically acceptable salt thereof.

14. W is CH ２ and Y is N and X is CH ２ 2. The compound of claim 1, wherein:

15. W is O and Y is CH ２ and X is CH ２ 2. The compound of claim 1, wherein:

16. Z is aryl, wherein the aryl is unsubstituted or is selected from the group consisting of halogen, —CN, —OH, C １ -C ６ Alkyl, heterocycloalkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkynyl, heteroaryl or C １ -C ６ substituted with 1, 2, or 3 substituents independently selected from the group consisting of haloalkoxy, wherein the heterocycloalkyl, C １ -C ６ Alkynyl or C ３ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is unsubstituted or substituted with an oxo group, -CN or -OH.

17. Z is heteroaryl, wherein the heteroaryl is unsubstituted or is selected from the group consisting of —CN, —OH, phenyl, halogen, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -COC １ -C ６ Alkyl, -COOC １ -C ６ Alkyl, -SC １ -C ６ Alkyl, oxo, C ３ -C ６ Cycloalkyl, heterocycloalkyl, CONH(C １ -C ６ alkyl), CONH ２ , CON(C １ -C ６ alkyl) ２ or heteroaryl, wherein the phenyl, C １ -C ６ The alkoxy or heteroaryl may be unsubstituted or may be substituted with halogen, C １ -C ６ Haloalkyl, heterocycloalkyl or C １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with alkyl.

18. Z is heteroaryl, wherein the heteroaryl is 【Transformation 3】 18. The compound of claim 17, wherein:

19. Z is heteroaryl, wherein the heteroaryl is 【Chemistry 4】 【change】 【change】 18. The compound of claim 17, wherein:

20. Z is SO ２ aryl, wherein the SO ２ Aryl is unsubstituted or substituted with halogen, —CN or C １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with alkyl.

21. Z is -COaryl, where the -COaryl is unsubstituted or is selected from the group consisting of halogen, -CN, -OH, C １ -C ６ Alkyl, heterocycloalkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkynyl, heteroaryl and C １ -C ６ substituted with 1, 2, or 3 substituents independently selected from the group consisting of haloalkoxy, wherein the heterocycloalkyl, C １ -C ６ Alkynyl or C ３ -C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is unsubstituted or substituted with an oxo group, -CN or -OH.

22. Z is —COheteroaryl, wherein the —COheteroaryl is 【Transformation 5】 【change】 【change】 【change】 2. The compound of claim 1, wherein:

23. Z is, 【Transformation 6】 2. The compound of claim 1, wherein:

24. Z is -COOCH ３ , —COOcyclobutyl, —COcyclohexane, —COcyclopentane, or 【Transformation 7】 2. The compound of claim 1, wherein:

25. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is -CONHaryl.

26. Z is —COheterocycloalkyl, wherein the —COheterocycloalkyl is 【Transformation 8】 2. The compound of claim 1, wherein:

27. Z is aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO ２ heterocycloalkyl, wherein the aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO ２ Heterocycloalkyl is unsubstituted or substituted with -CN, -OH, phenyl, halogen, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -COC １ -C ６ Alkyl, C １ -C ６ Alkynyl, -COOC １ -C ６ Alkyl, -SC １ -C ６ Alkyl, oxo, C ３ -C ６ Cycloalkyl, heterocycloalkyl, -CONH(C １ -C ６ alkyl), -CONH ２ , -CON(C １ -C ６ alkyl) ２ and heteroaryl, wherein the phenyl, heterocycloalkyl, C １ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C １ -C ６ The alkoxy or heteroaryl may be unsubstituted or may be substituted with an oxo group, —CN, —OH, halogen, C １ -C ６ Haloalkyl, heterocycloalkyl or C １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with alkyl.

28. Formula IV: 【Chemistry 9】 [During the ceremony, A is aryl, heteroaryl, heterocycloalkyl or C ３ -C ６ is cycloalkyl; R １ Each occurrence of is -OH, C １ -C ６ AlkylOH, —CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, halogen, -NH ２ , -N(C １ -C ６ alkyl) ２ , —NH(C １ -C ６ alkyl) and C １ -C ６ independently selected from the group consisting of alkoxy; Z is —CN, aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl, —SO ２ Heterocycloalkyl, —COOC １ -C ６ Alkyl or -COOC ３ -C ６ cycloalkyl, wherein the aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, -C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO ２ Heterocycloalkyl is unsubstituted or substituted with -CN, -OH, halogen, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl, C １ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -COOC １ -C ６ Alkyl, -COC １ -C ６ Alkyl, -SC １ -C ６ Alkyl, oxo, C ３ -C ６ Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -CONH(C １ -C ６ alkyl), -CONH ２ and -CON(C １ -C ６ alkyl) ２ and wherein the heteroaryl, heterocycloalkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkynyl or C １ -C ６ The alkoxy may be unsubstituted or substituted with halogen, —CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, —OH, and heterocycloalkyl; and m is 0, 1, 2 or 3. or a pharmaceutically acceptable salt thereof.

29. Formula V: 【Chemistry 10】 [During the ceremony, R １ Each occurrence of is -OH, C １ -C ６ AlkylOH, —CN, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, halogen and C １ -C ６ independently selected from the group consisting of alkoxy; Z is —CN, aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl, —SO ２ Heterocycloalkyl, —COOC １ -C ６ Alkyl or -COOC ３ -C ６ cycloalkyl, wherein the aryl, C １ -C ６ Alkylaryl, —COaryl, —CONHaryl, —SO ２ Aryl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl C ３ -C １０ Cycloalkyl, -COC ３ -C １０ Cycloalkyl, -CONHC ３ -C １０ Cycloalkyl, —SO ２ C ３ -C １０ Cycloalkyl, heteroaryl, C １ -C ６ Alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO ２ Heteroaryl, heterocycloalkyl, C １ -C ６ Alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO ２ Heterocycloalkyl is unsubstituted or substituted with -CN, -OH, halogen, C １ -C ６ Alkyl CN, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl, C １ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -COOC １ -C ６ Alkyl, -COC １ -C ６ Alkyl, -SC １ -C ６ Alkyl, oxo, C ３ -C ６ Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -CONH(C １ -C ６ alkyl), -CONH ２ , -CON(C １ -C ６ alkyl) ２ and wherein the heteroaryl, heterocycloalkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkynyl or C １ -C ６ The alkoxy may be unsubstituted or substituted with halogen, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ substituted with 1 to 2 substituents independently selected from the group consisting of alkoxy, OH, and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

30. The following structure: 【Chemistry 11】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

31. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a method of treating RIPK1-dependent inflammation and cell death that occurs in genetic and sporadic diseases, said method comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

32. 10. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a method of treating amyotrophic lateral sclerosis, said method comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

33. 10. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating amyotrophic lateral sclerosis in a patient in need thereof.

34. 10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. 10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

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