WO2013148851A1 - Compounds for treating neurodegenerative diseases - Google Patents

Description

COMPOUNDS FOR TREATING NEURODEGENERATIVE DISEASES

BACKGROUND OF THE INVENTION

[0001] PRIORITY OF INVENTION

[0002] This application claims priority to United States Provisional Application Number

61/616329 that was filed on 27 March 2012. The entire content of this provisional application is hereby incorporated herein by reference.

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to organic compounds useful for inhibition of β- secretase enzymatic activity and the therapy and/or prophylaxis of neurodegenerative diseases associated therewith. More particularly, certain tricyclic compounds useful in the treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease, are provided herein.

[0005] DESCRIPTION OF THE STATE OF THE ART

[0006] Alzheimer's disease ("AD") is a neurological disorder thought to be primarily caused by amyloid plaques, an accumulation of abnormal protein deposits in the brain. It is believed that an increase in the production and accumulation of amyloid beta peptides (also referred to as "Αβ" or "A-beta") in plaques leads to nerve cell death, which contributes to the development and progression of AD. Loss of nerve cells due to amyloid plaques in strategic brain areas, in turn, causes reduction in the neurotransmitters and impairment of memory. The proteins principally responsible for the plaque build up include amyloid precursor protein ("APP") and presenilin I and II ("PSI" and "PSII"). Mutations in each of these three proteins have been observed to enhance proteolytic processing of APP via an intracellular pathway that produces Αβ peptides ranging from 39 to 43 amino acids. The Αβ 1-42 fragment has a particularly high propensity of forming aggregates due to two very hydrophobic amino acid residues at its C-terminus. Thus, Αβ 1-42 fragment is believed to be mainly responsible for the initiation of neuritic amyloid plaque formation in AD and is therefore actively being pursued as a therapeutic target. Anti-Αβ antibodies have been shown to reverse the histologic and cognitive impairments in mice which overexpress Αβ and are currently being tested in human clinical trials. Effective treatment requires anti-Αβ antibodies to cross the blood-brain barrier ("BBB"), however, antibodies typically cross the BBB very poorly and accumulate in the brain in low concentration.

[0007] Different forms of APP range in size from 695-770 amino acids, localize to the cell surface, and have a single C-terminal transmembrane domain. Αβ is derived from a region of APP adjacent to and containing a portion of the transmembrane domain. Normally, processing of APP by a-secretase cleaves the midregion of the Αβ sequence adjacent to the membrane and releases a soluble, extracellular domain fragment of APP from the cell surface referred to as APP-a. APP-a is not thought to contribute to AD. On the other hand, pathological processing of APP by the proteases β-secretase (also referred to as "β-site of APP cleaving enzyme" ("BACE-1 "), memapsin-2 and Aspartyl Protease 2 ("Asp2")) followed by γ-secretase cleavage, at sites which are located N-terminal and C-terminal to the α-secretase cleavage site, respectively, produces a very different result than processing at the a site, i.e. the release of amyloidogenic Αβ peptides, in particular, Αβ 1 -42. Processing at the β- and γ-secretase sites can occur in both the endoplasmic reticulum and in the endosomal/lysosomal pathway after reinternalization of cell surface APP. Dysregulation of intracellular pathways for proteolytic processing may be central to the pathophysiology of AD. In the case of amyloid plaque formation, mutations in APP, PS1 or PS2 consistently alter the proteolytic processing of APP so as to enhance Αβ 1-42 formation.

[0008] The initial processing of APP by β-secretase results in a soluble N-APP, which has recently been implicated in neuronal cell death through a pathway independent of amyloid plaque formation. N-APP is involved in normal pruning of neurons in early development in which relatively unused neurons and their nerve-fiber connections (axons) wither and degenerate. Recently, however, it has been shown that N-APP binds to and activates the apoptotic death receptor 6 ("DR6") in vitro, which is expressed on axons in response to trophic factor (e.g., nerve growth factor) withdrawal resulting in axonal degeneration. The aging process can lead to a reduction in the levels of growth factors in certain areas of the brain and/or the ability to sense growth factors. This in turn would lead to the release of N-APP fragment by cleavage of APP on neuronal surfaces, activating nearby DR6 receptors to initiate the axonal shrinkage and neuronal degeneration of Alzheimer's.

[0009] See also, Rauk, Arvi. "The chemistry of Alzheimer's disease." Chem. Soc. Rev.

38 (2009): p. 2698-2715; Vassar, Robert, Dora M. Kovacs, Riqiang Yan and Philip C. Wong. "The β-Secretase Enzyme BACE in Health and Alzheimer's disease: Regulation, Cell Biology, Function, and Therapeutic Potential." J. Neurosci. 29(41) (2009): 12787-12794; and Silvestri, Romano. "Boom in the Development of Non-Peptidic β-Secretase (BACE1) Inhibitors for the Treatment of Alzheimer's Disease." Medicinal Research Reviews. Vol. 29, No. 2 (2009): p. 295- 338.

[0010] BACE-1 inhibitors include WO 201 1/072064, WO 201 1/123674 and WO

201 1/130741. [0011] Since β-secretase cleavage of APP is essential for both amyloid plaque formation and DR6-mediated apoptosis, it is a key target in the search for therapeutic agents for treating AD.

SUMMARY OF THE INVENTION

[0012] In one aspect of the present invention there is provided novel compounds having the general Formula I:

and stereoisomers, diastereomers, enantiomers, tautomers and pharmaceutically acceptable salts thereof, wherein W, X X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0013] In another aspect of the invention, there are provided pharmaceutical compositions comprising compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX and X and a pharmaceutically acceptable carrier, diluent or excipient.

[0014] In another aspect of the invention, there is provided a method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.

[0015] In another aspect of the invention, there is provided a method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.

[0016] In another aspect of the invention, there is provided a use of a compound of

Formula I, II, III, IV, V, VI, VII, VIII, IX and X in the manufacture of a medicament for the treatment of neurodegenerative diseases, such as Alzheimer's disease.

[0017] In another aspect of the invention, there is provided a use of a compound of

Formula I, II, III, IV, V, VI, VII, VIII, IX and X in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

[0018] Another aspect provides intermediates for preparing compounds of Formula I, II,

III, IV, V, VI, VII, VIII, IX and X. Certain compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX and X may be used as intermediates for other compounds of Formula [0019] Another aspect includes processes for preparing, methods of separation, and methods of purification of the compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying structures and formulas. While enumerated embodiments will be described, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

[0021] DEFINITIONS

[0022] The term "alkyl" includes linear or branched-chain radicals of carbon atoms.

Some alkyl moieties have been abbreviated, for example, methyl ("Me"), ethyl ("Et"), propyl ("Pr") and butyl ("Bu"), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1 -butyl or n-butyl ("n-Bu"), 2 -methyl- 1 -propyl or isobutyl ("i-Bu"), 1-mefhylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu") and the like. The abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol ("MeOH") or ethanol ("EtOH").

[0023] Additional abbreviations used throughout the application may include, for example, benzyl ("Bn"), phenyl ("Ph") and acetate ("Ac").

[0024] The terms "alkenyl" and "alkynyl" also include linear or branched-chain radicals of carbon atoms.

[0025] The term "alkoxy" means the group -O(alkyl), wherein the alkyl is linear or branched-chain. The alkyl may be substituted by the same substituents as the "substituted alkyl" group. Q-C6 alkoxy means -0(C!-C alkyl).

[0026] The terms "heterocycle" and "heterocyclic" include four to seven membered rings containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain instances, these terms may be specifically further limited, such as, "five to six membered heterocyclic" only including five and six membered rings. [0027] The term "heteroaryl" includes five to six membered aromatic rings containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain instances, these terms may be specifically further limited, such as, five to six membered heteroaryl, wherein the heteroaryl contains one or two nitrogen heteroatoms.

[0028] The term "optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different. In a particular embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents. In another embodiment, an optionally substituted group has 3 substituents. In another embodiment, an optionally substituted group has 0 to 3 substituents. In another embodiment, an optionally substituted group has 0 to 2 substituents. In another embodiment, an optionally substituted group has 1 to 3 substituents. In another embodiment, an optionally substituted group has 1 to 2 substituents.

[0029] The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0030] The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[0031] The phrase "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. [0032] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.

[0033] The compounds described herein also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds described herein and/or for separating enantiomers of compounds described herein.

[0034] The term "mammal" means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[0035] TRICYCLIC COMPOUNDS

[0036] Provided herein are compounds, and pharmaceutical formulations thereof, that are potentially useful in the treatment of diseases, conditions and/or disorders modulated by BACE-1.

[0037] One embodiment rovides compounds of Formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

W is a bond or CH₂;

Y is O, S or NR^a;

Z is a CH₂ or C=0;

Xi is selected from O, S, S(O), S0₂, NR^b and CHR^b;

X₂ is selected from CR⁶ and N;

R 1' and R 2 are independently selected from hydrogen and Q-Q alkyl;

R is selected from hydrogen and C_!-C₃ alkyl;

R⁴ is selected from hydrogen, halogen, CN, Q-C6 alkyl, Ci-C₆ alkoxy, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen;

R⁵ is selected from Q-C6 alkyl, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, C]-C₆ alkyl optionally substituted with halogen, C₃-C₆ cyclopropyl and Cj-C₆ alkoxy optionally substituted with one or more R^c groups;

R⁶ is selected from hydrogen, halogen, C C₆ alkyl and C]-C6 alkoxy;

R^a is C₁-C3 alkyl;

R^b is selected from hydrogen, halogen and Q-Q alkyl; and

R^c is selected from oxo and phenyl.

[0038] In certain embodiments of Formula I:

W is a bond;

Y is O or S;

Z is CH₂;

Xi is O;

X₂ is CR⁶;

1 2

R and R are hydrogen;

R is selected from hydrogen and C!-C₃ alkyl;

R⁴ is selected from hydrogen, halogen, CN, Cj-C₆ alkyl, C C₆ alkoxy, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen;

R⁵ is selected from C!-C₆ alkyl, C₃-C cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, C C₆ alkyl optionally substituted with halogen, C₃-C₆ cyclopropyl and C C₆ alkoxy optionally substituted with one or more R^c groups;

R⁶ is selected from hydrogen and CrC₆ alkoxy; and

R^c is selected from oxo and phenyl.

[0039] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula II:

II

wherein W, X_h X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein. [0040] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula HI:

wherein W, X_1; X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0041] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula IV:

IV

wherein W, X_1? X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0042] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula V:

wherein W, X,, X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0043] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula VI:

VI

wherein W, X X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0044] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula VII:

wherein W, X_1? X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0045] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula VIII:

VIII

wherein W, X_1? X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0046] In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula IX:

wherein W, X X₂, Y, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0047] In certain embodiments, (a) Y is S, Z is CH₂ and W is a bond; (b) Y is O, Z is

CH₂ and W is a bond; (c) Y is NR^a, Z is C=0 and W is a bond; (d) Y is NR^a, Z is C=0 and W is CH₂; or (e) Y is S, Z is CH₂ and W is CH₂. [0048] In certain embodiments, Y is O or S, Z is CH₂ and W is a bond. In certain embodiments, Y is O, Z is CH₂ and W is a bond. In certain embodiments, Y is S, Z is CH₂ and W is a bond.

[0049] In certain embodiments, Y is NR^a, Z is C=0 and W is a bond.

[0050] In certain embodiments, W is a bond. When W is a bond, the compounds of

Formula I have the structure of Formula X:

[0051] In certain embodiments, Xi is selected from O, S, S(O), S0₂, NR^b and CHR^b. In certain embodiments,

is O.

[0052] In certain embodiments, X₂ is selected from CR⁶ and N. In certain embodiments,

X₂ is CR⁶. In certain embodiments, X₂ is N. In certain embodiments, R⁶ is selected from hydrogen, halogen, C C₆ alkyl and C C alkoxy. In certain embodiments, R⁶ is selected from hydrogen and Ci-C₆ alkoxy. In certain embodiments, R⁶ is selected from hydrogen and methoxy. In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is methoxy.

[0053] In certain embodiments, R¹ and R² are independently selected from hydrogen and

C!-C₆ alkyl. In certain embodiments, R¹ and R² are independently selected from hydrogen and

1 2 1 2 methyl. In certain embodiments, R and R are hydrogen. In certain embodiments, R and R are methyl. In certain embodiments, R¹ is selected from hydrogen and methyl. In certain embodiments, R is selected from hydrogen and methyl.

[0054] In certain embodiments, R³ is selected from hydrogen and C C₃ alkyl. In certain embodiments, R is selected from hydrogen and methyl. In certain embodiments, R is hydrogen. In certain embodiments, R is methyl.

[0055] In certain embodiments, R⁴ is selected from hydrogen, halogen, CN, C C₆ alkyl,

C C6 alkoxy, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen. In certain embodiments, R⁴ is selected from hydrogen, halogen, CN, CpC₆ alkyl, Ci-Ce alkoxy optionally substituted with halogen, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl optionally substituted with halogen, and a 5 to 6 membered heteroaryl optionally substituted with halogen. In certain embodiments R⁴ is a heteroaryl optionally substituted with halogen, wherein the heteroaryl contains one, two or three heteroatoms selected from O, N and S. In certain embodiments R⁴ is a heteroaryl optionally substituted with halogen, wherein the heteroaryl contains one or two N heteroatoms. In certain embodiments R⁴ is a heteroaryl optionally substituted with halogen, wherein the heteroaryl is selected from pyridine and pyrimidine. In certain embodiments, R⁴ is selected from hydrogen, Br, CN, ethyl, isopropyl, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, 3-chloro-5-fluorophenyl, pyrimidin-5-yl, 5-fluoropyridin-3-yl and 5- chloropyridin-3-yl.

[0056] In certain embodiments, R⁵ is selected from C_!-C₆ alkyl, C₃-C₆ cycloalkyl, a 3 to

6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, C C6 alkyl optionally substituted with halogen, C₃-C₆ cyclopropyl and Q-Ce alkoxy optionally substituted with one or more R^c groups. In certain embodiments, R⁵ is selected from Q-C₆ alkyl, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or two groups selected from halogen, hydroxyl, C)-C6 alkyl optionally substituted with halogen, C₃-C₆ cyclopropyl and C C₆ alkoxy optionally substituted with one R^c group. In certain embodiments, R^c is selected from oxo and phenyl. In certain embodiments, R⁵ is a 3 to 6 membered heterocyclyl, wherein the heterocyclyl contains one or two heteroatoms selected from O, N and S. In certain embodiments, R⁵ is a 3 to 6 membered heterocyclyl, wherein the heterocyclyl contains one heteroatom selected from O and N. In certain embodiments, R⁵ is a 3 to 6 membered heterocyclyl, wherein the heterocyclyl is selected from oxetane, THP and pyrrolidine. In certain embodiments, R⁵ is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one, two or three heteroatoms selected from O, N and S. In certain embodiments, R⁵ is a 5 to 6 membered heteroaryl, wherein the heteroaryl contains one or two heteroatoms selected from O, N and S. In certain embodiments, R⁵ is a 5 to 6 membered heteroaryl, wherein the heteroaryl is selected from oxazole, isoxazole, imidazole, pyridine, pyrazine, pyrimidine and thiazole. In certain embodiments, R⁵ is a 9 to 10 membered bicyclic heteroaryl, wherein the heteroaryl contains one, two or three heteroatoms selected from O, N and S. In certain embodiments, R⁵ is a 9 to 10 membered bicyclic heteroaryl, wherein the heteroaryl contains one N heteroatom. In certain embodiments, R⁵ is a 9 to 10 membered bicyclic heteroaryl, wherein the heteroaryl is indole. [0057] In certain embodiments, R⁵ is selected from methyl, tert-butyl, neopentyl, 2- fluoropropan-2-yl, 1 ,1-difluoroethyl, 2-hydroxypropan-2-yl, l ,l ,l-trifluoro-2-methylpropan-2- yl, 1 -hydroxy-2-methylpropan-2-yl, difluoromethyl, cyclopropylmethyl, 2-methoxyethyl, methoxymethyl, (benzyloxy)methyl, methylacetate, 1-methylcyclopropyl, 1- (trifluoromethyl)cyclopropyl, 3-methyloxetan-3-yl, tetrahydropyran-4-yl, 2-methylpyrrolidin-2- yl, phenyl, 4-(difiuoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 4- chloro-3-methoxyphenyl, 2-methyloxazol-4-yl, 2-methyloxazol-4-yl, 5-methyloxazol-4-yl, 4- methyloxazol-5-yl, 5-methylisoxazol-4-yl, 3-methylisoxazol-4-yl, 5-methylisoxazol-3-yl, 1- methylimidazol-5-yl, l-methylimidazol-4-yl, pyridin-2-yl, pyridin-3-yl, 5chloro-3- fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-chloropyridin-3-yl, 5-fluoropyridin-2-yl, 5- methylpyridin-2-yl, 3-chloro-5-(trifluoromethyl)pyridin-2-yl, 3-methoxy-5-

(trifluoromethyl)pyridin-2-yl, 5-methoxypyridin-2-yl, 3,5-difluoropyridin-2-yl, 3-fluoropyridin- 2-yl, 6-methylpyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-2-yl, 6-methoxypyridin-3- yl, 2-methylpyridin-4-yl, 5-methylpyrazine-2-yl, pyrimidin-4-yl, 2-methylthiazol-4-yl and 5- fluoroindol-2-yl.

[0058] In certain embodiments, R⁵ is Ci-C₆ alkyl optionally substituted with R^d, C₃-C₆ cycloalkyl optionally substituted with R^e, a 3 to 6 membered heterocyclyl optionally substituted with R^f, phenyl optionally substituted with R^g, a 5 to 6 membered heteroaryl optionally substituted with R^h, a 9 to 10 membered bicyclic heteroaryl optionally substituted with R¹. In certain embodiments, R^d is selected from halogen, hydroxyl, C3-C6 cycloalkyl, Cj-C₆ alkoxy optionally substituted with R°. In certain embodiments, R^d is selected from halogen, hydroxyl, cyclopropyl, methoxy, benzyloxy and acetate. In certain embodiments, R^d is selected from halogen, hydroxyl, cyclopropyl, methoxy, benzyloxy and acetate. In certain embodiments, R^e is selected from hydroxyl and C_\-C alkyl optionally substituted with halogen. In certain embodiments, R^e is selected from methyl, CF3 and hydroxyl. In certain embodiments, R^f is Q- C₆ alkyl. In certain embodiments, R^f is methyl. In certain embodiments, R⁸ is selected from halogen, Ci-C₆ alkyl optionally substituted with halogen and Ci-C^ alkoxy. In certain embodiments, R⁸ is selected from CI, CF₂H, methoxy and ethoxy. In certain embodiments, R^h is selected from halogen, C1-C6 alkyl optionally substituted with halogen, and C C₆ alkoxy. In certain embodiments, R^h is selected from CI, F, methyl, CF₃ and methoxy. In certain embodiments, R¹ is halogen. In certain embodiments, R¹ is F.

[0059] In certain embodiments, R^a is Ci-C₃ alkyl. In certain embodiments, R^a is methyl.

[0060] In certain embodiments, R^b is selected from hydrogen, halogen and C]-C₆ alkyl. [0061] It will be appreciated that certain compounds described herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present compounds.

[0062] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds described herein. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.

[0063] It will also be appreciated that certain compounds of Formula I may be used as intermediates for further compounds of Formula I.

[0064] It will be further appreciated that the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the compounds embrace both solvated and unsolvated forms.

[0065] SYNTHESIS OF COMPOUNDS

[0066] Compounds described herein may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, New York: Wiley 1967-2006 ed. (also available via the Wiley InterScience® website), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0067] For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0068] In preparing compounds of Formula I, protection of remote functionalities (e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9- fluorenylmethyleneoxycarbonyl ("Fmoc"). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[0069] METHODS OF SEPARATION

[0070] It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

[0071] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound {e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting {e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0072] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds described herein may be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral denvatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0073] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, cc-methyl-β- phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in formation of the diastereomeric salts.

[0074] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity." J. Org. Chem. Vol. 47, No. 21 (1982): pp. 4165-4167), of the racemic mixture, and analyzing the Ή NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).

[0075] By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Lough, W.J., Ed. Chiral Liquid Chromatography. New York: Chapman and Hall, 1989; Okamoto, Yoshio, et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase." J. of Chromatogr. Vol. 513 (1990): pp. 375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0076] ADMINISTRATION AND PHARMACEUTICAL FORMULATIONS

[0077] The compounds described herein may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

[0078] The compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.

[0079] Compounds of the invention may be administered prior to, concomitantly with, or following administration of other therapeutic compounds. Sequential administration of each agent may be close in time or remote in time. The other therapeutic agents may be anti- neurodegenerative with a mechanism of action that is the same as compounds of the invention, i.e., inhibit beta-secretase cleavage of APP, or a different mechanism of action, e.g., anti-Αβ antibodies. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.

[0080] A typical formulation is prepared by mixing a compound described herein and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et ah, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug {i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0081] One embodiment includes a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X, or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment provides a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0082] METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION

[0083] The compounds of the invention inhibit the cleavage of amyloid precursor protein by β-secretase which is implicated in diseases, in particular, neurodegenerative diseases such as Alzheimer's disease. In AD, processing of APP by β-secretase produces soluble N-APP, which activates extrinsic apoptotic pathways by binding to death receptor 6. Furthermore, APP that is processed by β-secretase is subsequently cleaved by γ-secretase, thereby producing amyloid beta peptides, such as Αβ 1-42 that form amyloid plaques, which contribute to nerve cell death. Compounds of the invention inhibit enzymatic cleavage of APP by β-secretase.

[0084] Accordingly, in an aspect of the invention, there is provided a method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.

[0085] In another aspect of the invention, there is provided a method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX and X.

[0086] In another aspect, there is provided the use of a compound of Formula I, II, III,

IV, V, VI, VII, VIII, IX and X in the manufacture of a medicament for the treatment of a neurodegenerative disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease.

[0087] In another aspect of the invention, there is provided a use of a compound of

Formula I, II, III, IV, V, VI, VII, VIII, IX and X in the treatment of neurodegenerative diseases. In one embodiment, the neurodegenerative disease is Alzheimer's disease.

EXAMPLES

[0088] The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein. The identity and purity of compounds were checked by LCMS and 1H NMR analysis.

[0089] Column chromatography was done on a Biotage system (Manufacturer: Dyax

Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) (unless otherwise stated). 1H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H-NMR spectra were obtained as CDC1₃, CD₃OD, D₂0, (CD₃)₂SO, (CD₃)₂CO, C₆D₆, CD₃CN solutions (reported in ppm), using tetramefhylsilane (0.00 ppm) or residual solvent (CDC1₃: 7.26 ppm; CD30D: 3.31 ppm; D₂0: 4.79 ppm; (CD₃)₂SO: 2.50 ppm; (CD₃)₂CO: 2.05 ppm; C₆D₆: 7.16 ppm; CD₃CN: 1.94 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0090] In the Examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.

[0091] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.

Biological Example 1

Cellular B ACE 1 Inhibition Assay

[0092] The BACE inhibition properties of the compounds of the invention may be determined by the following in vitro cellular Amyloidp 1-40 production assay.

[0093] Inhibition of Amyloidp 1 -40 production was determined by incubating cells with compound for 48 hours and quantifying the level of Amyloidp 1-40 using an homogeneous time-resolved fluorescence ("HTRF") immunoassay.

[0094] Materials and Methods: HEK-293 cells stably transfected with a DNA construct containing the coding sequence for the wild type APP695 sequence were grown in Dulbecco's Modified Eagle Medium ("DMEM") supplemented with 10% fetal bovine serum, penicillin/streptomycin and 150 μg/mL G418. Cells were plated in 96-well plates at 35,000 cells/well and allowed to attach for 8-12 hours. Media was changed to DMEM supplemented with 10% fetal bovine serum, penicillin/streptomycin 15 minutes prior to compound addition. Diluted compounds were then added at a final concentration of 0.5% DMSO. After 48 hours, 4 pL of media from each well was added to a corresponding well of a 384 well plate (Perkin Elmer Cat#6008280) containing the HTRF reagents. HTRF reagents were obtained from the CisBio Amyloidp 1-40 peptide assay kit (Cat# 62B40PEC) and were prepared as follows anti- peptide β (l-40)-Cryptate and anti-peptide β (l-40)-XL655 were stored in 2 plate aliquots at - 80°C. Diluent and Reconstitution buffer were stored at 4°C. Aliquots of the two antibodies were diluted 1 : 100 with Reconstitution buffer, and this mixture was diluted 1 :2 with Diluent. 12 pL of the reagent mixture was added to the required wells of the 384 well assay plate. The assay plate was incubated at 4°C for 17 hours and then analyzed for fluorescence at 665 and 620 nm. The reported IC50 below may be from a single assay or the mean of multiple assays.

[0095] The following compounds were tested in the above assay. Some compounds were tested more than once, and the average is reported below.

Example 1

N-f(2 ^a ,9a^V2-amino-7'-(pyrM

4,9'-xanthen] -2'-yl)pivalamide

[0096] Step A: A solution of 1 ,4-cyclohexanedione monoethylene ketal (50 g, 320 mmol), morpholine (30.7 mL, 352 mmol), and 4-methylbenzenesulfonic acid-monohydrate (1.22 g, 6.40 mmol) in toluene (320 mL, 1M) in a 500 mL round bottom flask was fitted with a Dean-Stark trap and a condensor, and then the reaction mixture was heated at 132°C (bath temperature) for 12 hours. The reaction was cooled to ambient temperature, concentrated in vacuo, and dried under high vacuum for greater than 24 hours to provide 4-(l ,4- dioxaspiro[4.5]dec-7-en-8-yl)morpholine (70 g, 280 mmol, 87% yield) as an oil.

[0097] Step B: A solution 4-(l ,4-dioxaspiro[4.5]dec-7-en-8-yl)morpholine (70 g, 261 mmol), 5-bromo-2-hydroxybenzaldehyde (52 g, 261 mmol) in toluene (131 mL, 261 mmol) was stirred at room temperature for 24 hours. A solid precipitated after 10 minutes of reaction. After 1 day, the mixture was filtered and washed with a minimal amount of toluene. The solid was dried in a vacuum oven at 50°C overnight. The solid was confirmed to be 7'-bromo-4a'- morpholino-l',3',4',4a',9',9a'-hexahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'-ol (73 g, 171 mmol, 66% yield), and was taken onto the next step without further purification.

[0098] Step C: A solution of 7'-bromo-4a^,-morpholino-l ',3',4^,,4a^,,9',9a'- hexahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'-ol (50 g, 1 17 mmol) in DCM (586 mL, 1 17 mmol) was cooled to 0°C, and Dess-Martin reagent (59.7 g, 141 mmol) was added. The mixture was stirred at room temperature for 2 hours, monitoring by TLC. The reaction mixture was diluted with DCM (1 L) and then slowly quenched with 2N NaOH. The mixture was poured into a separatory funnel, rinsing the flask with DCM and water. The organic layer was washed successively with 2N NaOH (2 X 400-500 mL), 2N HC1 (2 X 300-400mL), water (1 X 300-400 mL), brine (1 X 400-500 mL), dried (Na₂S0₄) and concentrated to afford a solid, which was triturated with ether to afford 7'-bromo-3',4'-dihydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'( H)- one (38g, 1 13 mmol, 96%).

[0099] Step D: A solution of 7'-bromo-3',4'-dihydrospiro[[l ,3]dioxolane-2,2'-xanthen]-

9'(l 'H)-one (34 g, 101 mmol) in THF (1008 mL, 101 mmol) (2L round bottom flask) was cooled to -78°C, and L-Selectride® (151 mL, 151 mmol; 1.0M in THF) was added dropwise. The reaction was stirred at -78°C for 2 hours and then quenched at -78°C with NH4C1 (250 mL, saturated). The suspension was stirred vigorously while warming to room temperature. The reaction mixture was diluted with ethyl acetate (500 mL) and water (500 mL) with constant stirring. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (3 X). The combined organic layers were dried (Na2S04) and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 40% DCM/hexanes to 40% DCM/ethyl acetate gradient to afford 7'-bromo-l ',4^,,4a',9a'- tetrahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(3'H)-one (15.7 g, 46.3 mmol, 45.9 % yield). 2: 1 trans :cis by NMR.

[00100] Step E: Tebbe reagent (36 mL, 18 mmol) was added to a solution of 7'-bromo- l',4',4a',9a'-tetrahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(3^,H)-one (5.5 g, 16 mmol) in THF (162 mL, 16 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 1 hour, warming to room temperature and stirring for an additional 1 hour. The reaction mixture was cooled to 0°C, and methanol was slowly added until bubbling slowed down. Then 2N NaOH was added dropwise to precipitate salts, and addition was discontinued when drops of an aqueous phase appeared on sides of the flask. Na₂S0₄ was then added to this stirring mixture, and the reaction mixture was filtered, washing thoroughly with ether. The filtrate was concentrated. The residue was purified by flash chromatography, eluting with a gradient of 5%-15% ethyl acetate hexanes to afford (4a ,9a'i?)-7'-bromo-9^,-methylene-l ',3',4',4a^,,9',9a'-hexahydrospiro[[l ,3]dioxolane- 2,2'-xanthene]. Cis elutes first, trans last.

[00101] Step F: Iodine (18.8 g, 74.1 mmol) was added to a suspension of thiocyanatosilver (14.8 g, 89.0 mmol) in acetonitrile (30 mL) and tetrahydrofuran (30 mL) at 0°C, and the resulting mixture was stirred for 1 minute. (4a'S,9a'i?)-7'-bromo-9'-methylene- ,3',4',4a',9',9a'-hexahydrospiro[[l ,3]dioxolane-2,2'-xanthene] (10.0 g, 29.7 mmol) as a solid was quickly added to this mixture, and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered, NH4OH (30 ml) was added, and the filtrate was stirred at room temperature overnight. The suspension was poured into Na₂S20₃ (saturated), and the aqueous layer was extracted with ethyl acetate (2 X) and DCM (2 X). The combined organic layers were dried and concentrated to afford (4a'S,9'a ?)-7'-bromo-3',4',4'a,9'a-tetrahydro- l 'H,2"H-dispiro[l,3-dioxolane-2,2'-xanthene-9',3"-[l ,4]thiazole]-5"-amine (7.3 g, 17.7 mmol, 60%).

[00102] Step G: A solution of (4a'5,9'ai?)-7'-bromo-3',4^,,4^,a,9^,a-tetrahydro-l 'H,2"H- dispiro[l,3-dioxolane-2,2'-xanthene-9',3"-[l ,4]thiazole]-5"-amine (7.5 g, 18.2 mmol) in 4N HC1 (aqueous, 91.2 mL, 182 mmol) and acetone (91.2 mL, 18.2 mmol) was heated at 60°C overnight. The reaction mixture was concentrated and washed with ether. The aqueous layer was separated, then basified with KOH pellets and extracted with DCM/MeOH (3: 1 , 3 X). The combined organic layers were dried and concentrated to afford (4a'S,9a'iZ)-2-amino-7'-bromo- l',4^,,4a',9a^,-tetrahydro-5H-spiro[thiazole-4,9^,-xanthen]-2'(3'H)-one (6.16 g, 16.8 mmol, 92%). [00103] Step H: A suspension of (4a'S,9a'^)-2-amino-7'-bromo-l^,,4',4a^,,9a^,-tetrahydro- 5H-spiro[thiazole-4,9'-xanthen]-2'(3'H)-one (2.17 g, 5.91 mmol) in DCM (59 niL) was treated with TEA (1.24 niL, 8.86 mmol), followed by Boc₂0 (1.93 g, 8.86 mmol) at 60°C overnight. The reaction mixture was washed with brine, and the organic layer was dried and concentrated. The residue triturated in ether and collected by filtration to afford tert-butyl (4a'S,9a'i?)-7'- bromo-2'-oxo-r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (2.23 g, 4.77 mmol, 81%).

[00104] Step I: tert-Butyl (4a'S,9a'i?)-7'-bromo-2'-oxo-l',2',3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (0.500 g, 1.07 mmol) and ammonium acetate (1.24 g, 16.0 mmol) in MeOH (21 niL) was heated at 60°C for 1 hour. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (0.101 g, 1.60 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated, diluted with brine and extracted with EtOAc (3 X). The combined organic layers were dried (Na₂S0₄) and concentrated to afford tert-butyl (4a'5',9a'i?)-2'-amino-7'-bromo-l',2',3',4^,,4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (463 mg, 1.0 mmol, 92%).

[00105] Step J: TEA (0.0312 mL, 0.224 mmol) was added to a solution of tert-butyl (4a ,9a'i?)-2'-amino-7'-bromo-1^2^3^4^4a^9a'-hexahydro-5H-spiro[thiazole-4,9^,-xanthene]-2- ylcarbamate (0.100 g, 0.213 mmol) in DCM (2.13 ml) at room temperature, followed by the addition of pivaloyl chloride (0.029 mL, 0.235 mmol). After stirring at room temperature for 18 hours, the reaction mixture was loaded directly onto a flash column and eluted with a gradient of 10-100% EtOAc in DCM. The product-containing fractions were concentrated to afford tert- butyl (4a ,9a'i?)-7'-bromo-2^,-pivalamido-1^2^3',4',4a^,,9a^,-hexahydro-5H-spiro[thiazole-4,9'- xanthene]-2-ylcarbamate (57 mg, 0.10 mmol, 48%).

[00106] Step K: A solution of rt-butyl (4a'S,9a'/?)-7'-bromo-2'-pivalamido- l^,,2^,,3^,,4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (23 mg, 0.042 mmol), pyrimidin-5-ylboronic acid (5.42 mg, 0.044 mmol), Pd(PPh₃)₄ (2.41 mg, 0.002 mmol), Na₂C0₃ (2M aqueous) in dioxane (208 μί, 0.042 mmol) was degassed with nitrogen for 5 minutes, sealed in a vial and stirred at 80°C for 1 day. The reaction mixture was filtered through glass microfibre filter ("GF/F") paper, washing with methanol. The filtrate was concentrated. Boc deprotection: The residue was dissolved in DCM and treated with TFA (0.5 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated and then purified by C18 semi-preparative HPLC eluting with 5-95% ACN/H₂0 + 0.1% TFA. The product containing fractions were concentrated in vacuo to afford N-((2'S,4a'S,9a'i?)-2-amino-7'- (pyrimidin-5-yl)- 1 ',2',3 ',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2'-yl)pivalamide trifluoroacetic acid salt (9.2 mg, 0.02 mmol, 49%; racemic, single diastereomer, unknown thiazole configuration), m/z (APCI-pos) M+l = 452.1 (100%).

Ex mple 2

iV-((2'S.4a'S.9a'i? -2-amino-7'-(5-fluoropyridin-3-ylVl'.2'.3^,.4^,,4a^,.9a^,-hexahvdro-5H- spiro[thiazole-4,9'-xanthenl-2'-vDpivalamide

[00107] N-((2'S,4a'S,9a' ?)-2-Amino-7'-(5-fluoropyridin-3-yl)-l ^,,2',3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide trifluoroacetic acid salt ((0.006 g, 0.13 mmol, 20%; racemic, single diastereomer, unknown thiazole configuration) was prepared using a procedure analogous to Example 1 , Step J and K, substituting 5-fluoropyridin-3- ylboronic acid for pyrimidin-5-ylboronic acid, m/z (APCI-pos) M+l = 469.1 (100%).

Example 3

N-((2'S, ,4a ,9a^,i?)-2-amino-7'-(5-chloropyridin-3-vn-r.2'.3'.4'.4a'.9a'-hexahvdro-5H- spiro[thiazole-4,9'-xanthen]-2'-ylV2-fluoro-2-methylpropanamide

[00108] Step A: A mixture of rt-butyl (4a ,9a^,i?)-2'-amino-7'-bromo-l',2',3^,,4',4a^,,9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate, 2-fluoro-2-methylpropanoic acid (0.0322 g, 0.303 mmol), and triethylamine (0.106 mL, 0.758 mmol) in CH₂C1₂ (10 mL) at room temperature was treated with BOP-C1 (0.0353 g, 0.379 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with brine, and the organic layer dried (Na₂S0₄) and concentrated. The residue was purified by flash chromatography eluting with a gradient of 1-5% MeOH in DCM.

[00109] Step B: N-((2 ,4a ,9a^*i?)-2-Amino-7^,-(5-chloropyridin-3-yl)-l^,,2',3^,,4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2-fluoro-2-methylpropanamide trifluoroacetic acid salt (0.006 g, 0.13 mmol, 20%; racemic, single diastereomer, unknown thiazole configuration) was prepared using a procedure analogous to Example 1, Step K, substituting 5- chloropyridin-3-ylboronic acid for pyrimidin-5-ylboronic acid, m/z (APCI-pos) M+l = 489.1

(100%), 491.1 (35%). xample 4

N-( ^a .9a'i?V2-amino-7'-(5-chloropyridin-3-vn-l^,.2'3'.4',4a'.9a^,-hexahvdro-5H- spiro[thiazole-4,9'-xanthen1-2'-ylV2.2-difluoropropanamide

[00110] Step A: N-((4a'S,9a'/?)-2-Amino-7'-bromo-l^,,2^,,3^,,4^*,4a',9a^,-hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2'-yl)-2,2-difluoropropanamide (9 mg, 0.019 mmol, 17%) was prepared using a procedure analogous to Example 3, Step A, substituting 2,2-difluoropropanoic acid for 2-fluoro-2-methylpropanoic acid, then deprotection of the Boc group as in Example 1 , Step K.

[00111] Step B: N-((2 ,4a ,9a' ^)-2-Amino-7'-(5-chloropyridin-3-yl)-l^,,2',3',4^,,4a^,,9a^,- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2,2-difluoropropanamide trifluoroacetic acid salt (3.2 mg, 0.005 mmol, 37%; racemic, single diastereomer, thiazole configuration) was prepared using a procedure analogous to Example 1, Step J, substituting 5-chloropyridin-3- ylboronic acid for pyrimidin-5-ylboronic acid, m/z (APCI-pos) M+l = 493.1 (100%), 495.1 (35%).

mple 5

N-((4a'^.9a' ?)-2-amino-7'-(5-chloropyridin-3-yl -1 2',3'.4'.4a'.9a'-hexahvdro-5H-spiro[thiazole-

4,9'-xanthen1-2'-ylV2-methyloxazole-4-carboxamide

[00112] Step A: tert-Butyl (4a ,9a' ?)-2'-amino-7'-(5-chloropyridin-3-yl)-l',2',3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (70 mg, 0.112 mmol, 52%) was prepared using a procedure analogous to Example 1 , Step K (no deprotection), substituting tert- butyl (4a ,9a' ?)-7'-bromo-2'-oxo-l',2^,,3',4',4a^,,9a^,-hexahydro-5H-spiro[thiazole-4,9^,-xanthene]- 2-ylcarbamate (Example 1, Step Η) and 5-chloropyridn-3-yl boronic acid.

[00113] Step B: /ert-Butyl (4a'5,9a'7?)-7'-(5-chloropyridin-3-yl)-2'-(2-methyloxazole-4- carboxamido)- ,2^,,3^l,4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (15 mg, 0.025 mmol, 36%) was prepared using a procedure analogous to Example 3, Step A, substituting 2-methyloxazole-4-carboxylic acid. [00114] Step C: N-((4a^,S,9a'i?)-2-Amino-7'-(5-chloropyridin-3-yl)-l',2^,,3^,,4',4a^,,9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2-methyloxazole-4-carboxamide

trifluoroacetic acid salt (5.0 mg, 0.008 mmol, 34%; racemic, mixture of diastereomers) was prepared using a procedure analogous to Example 1 , Step K, Boc deprotection. m/z (APCI-pos) M+l = 51 1.1 (100%), 512.1 (35%).

Exam le 6

N-((2'S.4a^,S.9a'igV2-amino-7^,-(5-chloropyridin-3-yl)-l^,.2',3'.4'.4a'.9a'-hexahvdro-5H- spiro[thiazole-4,9'-xanthenl-2'-yl)-2-hvdroxy-2-methylpropanamide

[00115] DIEA (0.031 mL, 0.18 mmol) was added to a mixture of tert-butyl (43'5,93'Λ)-2'- amino-7'-(5-chloropyridin-3-yl)-1^2 3 4^4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2- ylcarbamate (Example 5, Step A, 0.030 g, 0.060 mmol), 2-hydroxy-2-methylpropanoic acid (0.008 g, 0.072 mmol), and HATU (0.027 g, 0.072 mmol) in ACN (0.60 mL) at 0°C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with brine, and the organic layer was dried (Na₂S0₄) and concentrated. The residue was dissolved in DCM (1 mL) and treated with TFA (1 mL) for 1 h at room temperature. The mixture was concentrated, and the residue was purified by CI 8 semi-preparative HPLC with a gradient of 5- 95% ACN in water (+0.1% TFA) to afford N-((2 ,4a ,9a' ?)-2-amino-7^,-(5-chloropyridin-3-yl)- l',2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2-hydroxy-2- methylpropanamide trifluoroacetic acid salt (15 mg, 0.025 mmol, 36%; racemic, unknown configuration of single diastereomer). m/z (APCI-pos) M+l = 487.1 (100%), 489.1 (40%).

Example 7

N- .4a .9a' ^)-2-amino-7'- yrimidin-5-vn-1 2^3 4 4a'.9a'-hexahvdro-5H-st)irorthiazole- 4,9'-xanthen]-2'-yl)-2-fluoro-2-methylpropanamide

[00116] N-((2 ,4a'S,9a'i?)-2-Amino-7'-(pyrimidin-5-yl)-l',2^,,3^,,4^,,4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)-2-fluoro-2-methylpropanamide trifluoroacetic acid salt (3 mg, 0.005 mmol, 9%; racemic, unknown configuration of single diastereomer) was prepared using a procedure analogous to Example 3, Step B, substituting pyrimidin-5-ylboronic acid, m/z (APCI- pos) M+l = 456.2 (100%).

mple 8

N-r(2',S.4a' .9a'j?V2-amino-7'-(5-chloropyridin-3-vn-l'.2'.3^,.4'.4a'.9a^,-hexahvdro-5H- spiro [thiazole-4.9'-xanthen1 -2'-yl)- 1 -methylcyclopropanecarboxamide

[00117] Step A: N-((2'₁S,45,4a ,9a'J?)-2-Amino-7'-bromo-l^*,2^,,3^,,4^,,4a',9a^,-hexahydro-5H- spiro[thiazole-4,9'-xanthene]-2'-yl)-l -methylcyclopropanecarboxamide (10 mg, 0.018 mmol, 17%) was prepared using a procedure analogous to Example 3, Step A, substituting 1- methylcyclopropanecarboxylic acid.

[00118] Step B: N-((2^,S,4a^,5,9a^, ?)-2-amino-7'-(5-chloropyridin-3-yl)-l',2',3',4^,,4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)- 1 -methylcyclopropanecarboxamide (3 mg, 0.004 mmol, 24%: racemic, unknown thiazole stereochemistry) was prepared using a procedure analogous to Example 3, Step B. m/z (APCI-pos) M+l = 483.1 (100%), 485.1 (40%).

Exam le 9

N-((2 .4a .9a'/?)-2-Amino-7'-(5-chloropyridin-3-yl)-l\2'.3'.4'.4a'.9a'-hexahvdro-5H- spiro[thiazole-4,9'-xanthenl-2'-yl)pivalamide

[00119] Pivaloyl chloride (0.004 mL, 0.029 mmol)Step A: to a solution of tert-butyl (4S,4a'S,9a^,i?)-2'-amino-7'-(5-chloropyridin-3-yl)-l 2 3^4^4a 9a'-hexahydro-5H-spiro[thiazole 4,9'-xanthene]-2-ylcarbamate (Example 5, Step A, 0.014 g, 0.028 mmol) and TEA (0.004 mL, 0.029 mmol) in DCM (0.3 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, and the organic layer was separated, dried, and concentrated to afford tert-butyl (45',4a'5',9a^,i?)-7'-(5- chloropyridin-3-yl)-2'-pivalamido- ,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]- 2-ylcarbamate (7 mg, 0.012 mmol, 43%).

[00120] Step B: N-((2'S,4a^,5,9a'i?)-2-Amino-7'-(5-chloropyridin-3-yl)-l^,,2',3',4',4a^,,9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (4 mg, 0.007 mmol, 57%; racemic, unknown thiazole stereochemistry) was prepared using an analogous procedure to Example 1, Step K, Boc deprotection. m/z (APCI-pos) M+l = 485.1 (100%), 487.1 (35%).

Example 10

N-( 'S.4a'S.9a^,^V2-amino-7'-(5-cvanopyridin-3-vn-l^,.2^,.3'.4^,.4a'.9a'-hexahvdro-5H- spiro [thiazole-4,9'-xanthen1 -2'-yl)pivalamide

[00121] N-((2'S,4a ,9a'i?)-2-Amino-7'-(5-cyanopyridin-3-yl)-l',2',3',4',4a',9a'-hexahydro- 5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide trifluoroacetic acid salt (10 mg, 0.015 mmol, 16%; racemic, unknown thiazole configuration) was prepared using a procedure analogous to Example 1, Step K, substituting 5-cyanopyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 476.2 (100%).

Example 11

N-((2'S.4a'S.9a'igV2-amino-7'-(5-fluoropyridin-3-vn-l'.2'.3'.4'.4a'.9a^,-hexahvdro-5H- spiro[thiazole-4,9'-xanthen]-2'-yn-2-fluoro-2-methylpropanamide

[00122] N-((2 ,4a ,9a^)-2-Amino-7^,-(5-fluoropyridin-3-yl)-l^,,2',3',4',4a^,,9a^,-hexahydro- 5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2-fluoro-2-methylpropanamide trifluoroacetic acid salt (5 mg, 0.008 mmol, 14%; racemic, unknown thiazole configuration) was prepared using a procedure analogous to Example 3, Step B, substituting 5-fluoropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 473.1 (100%).

mple 12

N-((2 .4a .9a'^V2-amino-7'-(3-chloro-5-fluorophenvn-l'.2'.3'.4'.4a'.9a'-hexahvdro-5H- spiro thiazole-4,9'-xanthen]-2'-yl)pivalamide [00123] Step A: (4a ,9a'i?)-2-Amino-7'-(3-chloro-5-fluorophenyl)-r,4^*,4a',9a'-tetrahydro- 5H-spiro[thiazole-4,9'-xanthen]-2'(3'H)-one (77 mg, 0.185 mmol, 68%) was prepared from the product of Example 1, Step G, and 3-chloro-5-phenylboronic acid using the procedure in Example 1, Step K.

[00124] Step B: rt-Butyl (4S,4a'S,9a'i?)-7^,-(3-chloro-5-iluorophenyl)-2^,-oxo- r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (106 mg, 0.205 mmol, >99%) was prepared using an analogous procedure to Example 1 , Step H.

[00125] Step C: tert-Butyl (45,4a ,9a'i?)-2'-amino-7'-(3-chloro-5-fluorophenyl)- l',2^,,3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2-ylcarbamate (79 mg, 0.015 mmol, 74%) was prepared using an analogous procedure to Example 1 , Step I.

[00126] Step D: N-((2'S,4a'S,9a^)-2-Amino-7'-(3-chloro-5-fluorophenyl)-

1 ',2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide trifluoroacetic acid salt (1.5 mg, 0.003 mmol, 2%; racemic, unknown thiazole configuration) was prepared using an analogous procedure to Example 1, Step J, and Boc deprotection from Example 1, Step K. m/z

(APCI-pos) M+l = 502.2 (100%), 504.2 (40%).

Exam le 13

N-((2 .4a .9a'i?V2-amino-7^,-(pyrimidin-5-ylVl^,.2'.3'.4'.4a^,.9a'-hexahvdro-5H-spiroroxazole-

4,9'-xanthen]-2'-yl)pivalamide

[00127] Step A: In a 20-dram vial, a solution of iodine (1.66 g, 6.52 mmol) in THF (3.26 mL, 3.26 mmol) was added to a suspension of silver cyanate (1.96 g, 13.0 mmol) in acetonitrile (3.26 mL, 3.26 mmol). The resulting mixture was shaken for 60 seconds. This mixture was quickly poured into a solution of (4a'S,9a'i?)-7^,-bromo-9'-methylene-l',3',4^,,4a',9',9a'- hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (1.10 g, 3.26 mmol) in ether (32.6 mL, 3.26 mmol) at 0°C, rinsing the vial with acetonitrile (1 X). After 1 hour, the reaction mixture was filtered through GF/F paper, and to the filtrate was added a stir bar and NH₄OH (1.63 mL, 3.26 mmol). The resulting dark solution was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 2N NaOH, and the aqueous layer was extracted with ethyl acetate (3 X). The combined organic layers were dried and concentrated to afford a residue that was purified by flash chromatography, eluting with DCM/MeOH gradient (0-15%) to give (4'aS,9'ai^)-7'-bromo-3',4',4'a,9^,a-tetrahydro-l'H,2"H-dispiro[l,3-dioxolane-2,2^,- xanthene-9',3"-[l,4]oxazole]-5"-amine (0.850 g, 2.15 mmol, 66%).

[00128] Step B: A solution of (4'aS,9'ai?)-7'-bromo-3',4',4'a,9'a-tetrahydro-l'H,2^,,H- dispiro[l ,3-dioxolane-2,2'-xanthene-9',3"-[l,4]oxazole]-5"-amine (1.20 g, 3.04 mmol) in 2N HC1 (8.0 mL) and acetone (15 mL, 3.04 mmol) was heated at 55°C overnight. The mixture was basified with NaOH until a pH of greater than 10, and the mixture was extracted with ethyl acetate (3 X). The combined organic layers were dried and concentrated. The solid was purified by trituration with ether to give a solid corresponding to (4a'S,9a'i?)-2-amino-7'-bromo- l'^'^a'^a'-tetrahydro-SH-spirofoxazole^^'-xanthenl^^'HI-one (480 mg, 1.37 mmol, 45.0% yield).

[00129] Step C: A suspension of (4a'S,9a'7?)-2-amino-7'-bromo-l',4',4a',9a'-tetrahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (1.00 g, 2.85 mmol) in DCM (29 mL) at room temperature was treated with TEA (0.60 mL, 4.27 mmol), followed by Boc₂0 (0.932 g, 4.27 mmol). The reaction mixture was stirred at 60°C overnight, then washed with brine, and the organic layer was dried (Na₂S0₄) and concentrated to afford tert-butyl (4a'S,9a ?)-7'-bromo-2'- oxo-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2-ylcarbamate (1.19 g, 2.64 mmol, 93%).

[00130] Step D: rt-Butyl (4S,4a'S',9a^,i?)-2^,-amino-7'-bromo-l',2^,,3^,,4',4a',9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2-ylcarbamate (1.4 g, 3.10 mmol, >99%) was prepared using an analogous procedure to Example 1 , Step I.

[00131] Step E: N-((4a'S,9a'^)-2-Amino-7^,-bromo-l',2',3^,,4^,,4a',9a^,-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2'-yl)pivalamide was prepared using an analogous procedure to Example 1, Step J, and Boc deprotection from Example 1, Step (99 mg, 0.19 mmol, 86%).

[00132] Step F: N-((2'S,4a'S,9a' ?)-2-Amino-7'-(pyrimidin-5-yl)-l^,,2',3^,,4^,,4a',9a^*- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide trifluoroacetic acid salt (4 mg, 0.009 mmol, 5%; racemic, unknown oxazole stereochemistry) was prepared using an analogous procedure to Example 1, Step K, substituting pyrimidin-5-ylboronic acid, m/z (APCI-pos) M+l = 436.1 (100%). Exam le 14

N-((2W.4a .9a' V2-ammo-7'-(pyr^

4,9'-xanthen^~|-2'-yl)pivalamide

[00133] N-((2'S,4a ,9a'7?)-2-Amino-7'-^yrimidin-5-yl)-l 2 3',4^,,4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide trifluoroacetic acid salt (22 mg, 0.049 mmol, 56%; racemic, unknown thiazole stereochemistry) was prepared using an analogous procedure as Example 13. m/z (APCI-pos) M+l = 452.2 (100%).

le 15

N-((2 ^a .9a^,i?V2-amino-7'-bromo-l'.2^,.3^,.4'.4a'.9a'-hexahvdro-5H-spirorthiazole-4.9'- xanthen] -2'- yl)- 1 -(trifluoromethyl)cvclopropanecarboxamide

[00134] N-((2 ,4a'S,9a^,i?)-2-Amino-7'-bromo- 1 '^'^'^'^a'^a'-hexahydro-SH- spiro[thiazole-4,9'-xanthen]-2'-yl)-l-(trifluoromethyl) cyclopropanecarboxamide trifluoroacetic acid salt (5 mg, 0.008, 8%; racemic, unknown thiazole stereochemistry) was prepared using the procedure from Example 3, Step A, substituting l-(trifluoromethyl)cyclopropanecarboxylic acid, followed by Boc deprotection from Example 1, Step K. m/z (APCI-pos) M+l = 504.0 (100%), 506.0 (100%).

Example 16

N-r(2^, _lS.4a'S.9a'_J/?)-2-amino-7'-bromo-l'.2'.3^,.4^,.4a^,.9a'-hexahvdro-5H-spirorthiazole-4.9'- xanthen -2'-ylV3.3.3-trifluoro-2.2-dimethylpropanamide

[00135] N-((2^,S,4a'S,9a'i?)-2-Amino-7'-bromo-l^,,2^,,3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen] -2'-yl)-3 ,3 ,3 -trifluoro-2,2-dimethylpropanamide trifluoroacetic acid salt (5 mg, 0.008 mmol, 8%; racemic, unknown thiazole stereochemistry) was prepared using an analogous procedure to Example 15, substituting 3,3,3-trifluoro-2,2-dimethylpropanoic acid. (APCI-pos) M+l = 506.0 (100%), 508.0 (100%).

Example 17

N-((2 ,4a ,9a'J?)-2-amino-7'-(3-chloro-5-fluorophenvn-l'.2'.3',4'.4a',9a'-hexahvdro-5H- spiro oxazole-4.9'-xanthen1-2'-yl)-l-methylcyclopropanecarboxamide

[00136] N-((2 ,4a^,S,9a^, ^)-2-Amino-7^,-(3-chloro-5-fluorophenyl)-l^,,2^,,3^,,4^,,4a^,,9a^,- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-l-methylcyclopropanecarboxamide

tnfluoroacetic acid salt (9 mg, 0.017 mmol, 8%; racemic, unknown oxazole stereochemistry) was prepared using an analogous procedure as Example 12, substituting 1- methylcyclopropanecarboxylic acid, m/z (APCI-pos) M+l = 434.0 (100%), 436.0 (100%).

Example 18

N-((2'S,4a'S.9a'i?)-2-amino-7'-bromo-l^,.2^,.3'.4'.4a',9a'-hexahvdro-5H-spirorthiazole-4.9'- xanthen1-2'-yl)-5-chloro-3-fluoropicolinamide

[00137] N-((2 ,4a^,S,9a^)-2-Amino-7^,-bromo-r,2',3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)-5-chloro-3-fluoropicolinamide trifluoroacetic acid salt (5 mg, 0.008 mmol, 32%; racemic, unknown thiazole stereochemistry) was prepared using an analogous procedure to Example 15, substituting 5-chloro-3-fluoropicolinic acid, m/z (APCI- pos) M+l = 525.0 (100%), 527.0 (100%).

Example 19

N-((2 .4a .9a'i^ 2-amino-6'-methoxy-l',2' 4'.4a'.9a'-hexahvdro-5H-spiro[oxazole-4.9^,- xanthen]-2'-yl)-5-chloropicolinamide [00138] Step A: Oxalyl Chloride in DCM (2M) (52.90 mL, 105.8 mmol) was added to a mixture of 2-fluoro-4-methoxybenzoic acid (15.0 g, 88.16 mmol) in DCM (293.9 mL, 88.16 mmol) at 0°C. A few drops of DMF were added. This was stirred for 45 minutes. This was then concentrated down and taken up in THF and DCM. LHMDS (96.98 mL, 96.98 mmol) was added to a solution of l ,4-dioxaspiro[4.5]decan-8-one (13.77 g, 88.16 mmol) in THF in a new round bottom at -78°C. This was stirred for 10 minutes, followed by the addition of the acid chloride. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water. The organics were extracted with EtOAc twice, washed with brine and dried with Na₂S0₄. This was concentrated down, and the solid material was triturated with EtOAc to give 7-(2-fluoro-4-methoxybenzoyl)-l,4-dioxaspiro[4.5]decan-8-one (16.6 g, 53.84 mmol, 61.07% yield).

[00139] Step B: A mixture of 7-(2-fluoro-4-methoxybenzoyl)-l ,4-dioxaspiro[4.5]decan-8- one (16.6 g, 53.84 mmol) and K₂C0₃ (14.88 g, 107.7 mmol) in DMF (150 mL, 53.84 mmol) was stirred at room temperature for 2 hours. This was then worked up with EtOAc and water. The organics were extracted twice, washed with brine and dried with Na₂S0₄. This was then concentrated down to give 6'-methoxy-3',4'-dihydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(rH)- one (14.63 g, 50.75 mmol, 94.25% yield).

[00140] Step C: L-Selectride® (55.82 mL, 55.82 mmol) was added to a mixture of 6'- methoxy-3',4'-dihydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(rH)-one (14.63 g, 50.75 mmol) in DCM (169.2 mL, 50.75 mmol) at -78°C. This was stirred for 45 minutes. 0.5N Rochelle's salt solution was poured into the reaction. The mixture was then allowed to come to room temperature overnight. This was worked up with EtOAc and water. The organics were extracted with EtOAc twice, washed with brine and dried with Na₂S0₄. This was concentrated down and purified on a column using EtOAc:hexane to give (4a'5',9a'5)-6'-methoxy- ,4',4a',9a'- tetrahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(3'H)-one (1.1 g, 3.789 mmol, 7.467% yield).

[00141] Step D: Tebbe reagent (9.09 mL, 4.55 mmol) was added to a mixture of (4a ,9a^,5)-6'-methoxy-1 ^4^4a^9a'-tetrahydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9X3'H)-one (1.1 g, 3.79 mmol) in THF (18.9 mL, 3.79 mmol) at 0°C. This was then stirred overnight at room temperature. The mixture was quenched with MeOH and then 2N NaOH was added, and this was stirred for 1 hour. The mixture was filtered through GF/F paper, and the filtrate was worked up with EtOAc and water. The organics were extracted twice, washed with brine and dried with Na₂S0₄. This was then concentrated down and purified on a column using EtOAc:hexanes to give (4a ,9a'i?)-6^,-methoxy-9'-methylene-l^,,3^,,4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'- xanthene] (0.749 g, 2.60 mmol, 68.6% yield). [00142] Step E: I₂ (0.726 g, 2.86 mmol) was added to a mixture of silver cyanate (1.17 g, 7.80 mmol) and (4a'S,9a'i?)-6'-methoxy-9'-methylene-l ',3',4',4a^,,9^,,9a'- hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (0.75 g, 2.60 mmol) in THF (10.4 mL, 2.60 mmol) and some ACN. This was stirred at 0°C overnight. The mixture was filtered through GF/F paper. The filtrate was concentrated down, and a mixture of THF and ACN was added. Ν¾ΟΗ (1.86 mL, 26.0 mmol) was added, and this was stirred overnight. The mixture was partitioned between DCM and water. The organics were extracted with DCM twice, washed with brine and dried with Na₂S0₄. This was concentrated down and purified on a column to give the product (0.372 g, 1.07 mmol, 41.3% yield).

[00143] Step F: A mixture of the product of Step E (0.752 g, 2.17 mmol) and HC1 (10.9 mL, 21.7 mmol) in acetone (15 mL, 2.17 mmol) was refluxed overnight. The mixture was worked up with DCM and water. The organics were extracted with DCM twice, washed with brine and dried with Na₂S0₄. This was then concentrated down and purified on a column using DCM:MeOH:NH₄0H (90: 10: 1) to give (4a'S,9a'/?)-2-amino-6'-methoxy-l',4',4a',9a'-tetrahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (0.462 g, 1.53 mmol, 70.4% yield).

[00144] Step G: A mixture of (4a ,9a^*^)-2-amino-6'-methoxy-l^,,4',4a',9a'-tetrahydro-5H- spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (0.462 g, 1.53 mmol) and N¾OAc (1.77 g, 22.9 mmol) in MeOH (10.2 mL, 1.53 mmol; d. 0.791) was stirred at 60°C for 3 hours. This was then cooled to 0°C, and NaCNBH₃ (0.144 g, 2.29 mmol) was added. The mixture was stirred at room temperature overnight. 2N NaOH was added to the mixture, and this was sonicated and filtered. The solid was washed with water followed by hexanes. The solids were then collected to give (2 ,4a^, ₁S,9a^,i?)-6'-methoxy-l',2',3',4^,,4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2^*- diamine (0.437 g, 1.44 mmol, 94.3% yield).

[00145] Step H: A mixture of (2^,S,4a^,S,9a'i?)-6'-methoxy-l^,,2^,,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (0.150 g, 0.494 mmol), 5-chloropicolinic acid (0.195 g, 1.24 mmol), EDCI (0.237 g, 1.24 mmol) and HOBT (0.100 g, 0.742 mmol) in DMF (4.94 mL, 0.494 mmol) was stirred at room temperature for 3 hours. IN NaOH was then added, and the solids were filtered off and washed with water then hexanes. The material was dried and then taken up in MeOH and some 2M LiOH. The mixture was heated to 60°C overnight. The mixture was then diluted with NH₄C1 to give a solid. The solid was collected by filtration and then taken up in MeOH to be purified on preparative HPLC to give N-((2'S,4a'S,9a'/?)-2-amino-6'-methoxy- r,2',3',4^,,4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2^,-yl)-5-chloropicolinamide (0.0239 g, 0.0540 mmol, 10.9% yield) and the other diastereomer N-((2'S,4a'S,9a' )-2-amino-6'- methoxy- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2'-yl)-5- chloropicolinamide (0.0023 g, 0.00519 mmol, 1.05% yield).

Example 20

N-((2'S^R,4a'S.9a^ -2-amino-7'-cvano-l'.2'.3'.4'.4a'.9a'-hexahvdro-5H-spiro thiazole-4.9'- xanthen]-2'-yl)pivalamide

N-((2'i?.4^.4a .9a'i?)-2-amino-7'-cvano-l 2 3 4 4a 9a'-hexahvdro-5H-spirorthiazole-4

xanthen1-2'-yl)pivalamide

[00146] Step A: A solution of l,4-dioxaspiro[4.5]decan-8-one (100.0 g, 641 mmol), morpholine (61.4 g, 705 mmol), and 4-methylbenzenesulfonic acid-monohydrate (2.9 g, 15 mmol) in toluene (1000 mL) in a 2000 mL round bottom flask was fitted with a Dean-Stark trap and a condenser. The reaction mixture was stirred at 135°C for 16 hours. The reaction was cooled to room temperature, concentrated in vacuo to provide 4-(l,4-dioxaspiro[4.5]dec-7-en-8- yl)morpholine (144.0 g, crude) as an oil. It was used without further purification.

[00147] Step B: A solution of 4-(1,4^ΐοχ38ρΪΓθ[4.5^6ϋ-7-6η-8^1^θ ηο1ΐηε (144.0 g, crude), 5-bromo-2-hydroxylbenzaldehyde (128.2 g, 641 mmol) in toluene (300 mL) was stirred at room temperature for 24 hours. The mixture was filtered and washed with a minimal amount of toluene. The solid was dried in a vacuum oven at 50°C overnight to give 7'-bromo-4a'- morpholino-l',3',4',4a^,,9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'-ol (80.0 g, crude) as a solid.

[00148] Step C: A solution of 7'-bromo-4a'-morpholino-l',3',4^,,4a',9',9a'- hexahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'-ol (80.0 g, crude) in DCM (800 mL) was cooled to 0°C, and Dess-Martin reagent (95.4 g, 225 mmol) was added in portions. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (1L), then slowly quenched with 2N NaOH. The mixture was poured into a separatory funnel, rinsing the flask with DCM and water. The organic layer was washed successively with 2N NaOH (2 X 500 mL), 2N HC1 (2 X 500 mL), water (500 mL), brine (500 mL), dried and concentrated to afford a solid, which was triturated with ether to give the desired compound 7'-bromo-3',4'- dihydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'(l^,H)-one (54.0 g) as a solid. 1H NMR (400 MHz, CDC1₃) δ 8.30 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.09- 4.40 (m, 4H), 2.95-2.90 (m, 2H), 2.79 (s, 1H), 2.05- 2.01 (m, 2H). [00149] Step D: A solution of 7'-bromo-3',4'-dihydrospiro[[l,3]dioxolane-2,2'-xanthen]- 9'(l'H)-one (50 g, 149 mmol) in THF (800 mL) was cooled to -70°C, and L-Selectride® (1.0M in THF, 223 mL, 223 mmol) was added dropwise. The reaction was stirred at -70°C for 2 hours, then quenched at -70°C with saturated NH4CI (800 mL). The suspension was stirred vigorously while warming to room temperature. The reaction mixture was diluted with ethyl acetate (800 mL) and water (800 mL) with constant stirring. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (3 X 1L). The combined organic layers were dried and concentrated to afford the crude product which was purified by silica gel (hexanes:EtOAc, 15: 1 to 5:1) to give compound (4a'S 7'-bromo-l',4',4a',9a'- tetrahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'(3'H)-one (27.0 g, 54.0%) as a solid. 1H NMR (400 MHz, CDCI3) δ 7.97 (d, J = 2.8 Hz, 1H), 7.55 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.15-4.08 (m, 1H), 4.03-3.95 (m, 4H), 2.87-2.80 (m, 1H), 2.44-2.38 (m, 1H), 2.27-2.21 (m, 1H) , 2.14-2.04 (m, 1H), 1.88-1.83 (m, 1H), 1.70-1.66 (m, 1H), 1.50-1.45 (m, 1H).

[00150] Step E: Tebbe reagent (0.60M in toluene, 274 mL, 164 mmol) was slowly added at 0°C to a solution of (4a'S)-7'-bromo- ,4',4a^,,9a'-tetrahydrospiro[[l,3]dioxolane-2,2'-xanthen]- 9'(3'H)-one (37.0 g, 109 mmol) in THF (600 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by 2N NaOH, to this stirring mixture was added Na₂S0₄, and the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel (hexanes:EtOAc, 1 :40) to give (4a'5,9a'i?)-7'-bromo-9'-methylene- l^,,3^,,4',4a',9',9a^,-hexahydrospiro[[l,3]dioxolane-2,2^,-xanthene] (16.0 g, trans, 43.2% yield) as a solid. 1H NMR (400 MHz, CDC1₃) δ 7.62 (d, 1H), 7.25-7.22 (dd, J = 8.8, 2.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.48 (d, J = 2.4 Hz, 1H), 4.88 (d, J = 2.4 Ηζ,ΙΗ), 4.01-3.97 (m, 4H), 3.69-3.68 (m, 1H), 2.59 - 2.50 (m, 1H), 2.24 - 2.15 (m, 2H), 1.89 - 1.85 (m, 2H), 1.68 - 1.64 (m, 1H), 1.58 - 1.52 (m, 1H).

[00151] Step F: A solution of iodine (9.2 g, 36 mmol) in EtOAc (120 mL) was added dropwise to a suspension of AgSCN (7.0 g, 42 mmol) and (4a'S',9a'i?)-7'-bromo-9'-methylene- ,3',4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (10 g, 30 mmol) in acetonitrile (60 mL) and EtOAc (60 mL) at 0°C. After 3 hours, the reaction mixture was filtered through Celite®, washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (400 mL), and NH₄OH (100 mL, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and saturated NaHC0₃, and the aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organic layers were dried and concentrated to afford the crude product which was purified by column on silica gel (DCM:MeOH, 100:1 to 20:1) to give the solid (1 1.2 g, 93.3% yield). Ή NMR (400MHz, (CD₃)₂SO) δ 7.61 (d, J = 2.4 Hz, 1 H), 7.28 (d, J = 2.4, 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1 H), 6.50 (s, br, 2H), 4.04-3.85 (m, 6H), 3.60-3.57 (m, 2H), 2.1 1-2.09 (m, 1H), 1.99 -1.50 (m, 5H), 1.42-1.33 (m, 1H).

[00152] Step G: A solution of the product of Step F (1 1.2 g, 27 mmol) in 3N HC1 (150 raL), acetone (400 mL) and THF (50 mL) was heated at 60°C for 16 hours. The mixture was basified with NaOH until pH greater than 10, and the mixture was extracted with EtOAc (3 X 500 mL). The combined organic layers were dried, concentrated, and purified by trituration with hexanes to give (4a'S,9a'i?)-2-amino-7'-bromo-r,4',4a',9a'-tetrahydro-5H-spiro[thiazole-4,9'- xanthen]-2'(3'H)-one (8.2 g, 81.8% yield) as a solid. 1H NMR (400MHz, (CD₃)₂SO) δ 7.63 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4, 8.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.57 (s, br, 2H), 4.37-3.31 (m, 1H), 3.62-3.52 (m, 2H), 2.34-2.19 (m, 5H), 1.38 -1.21 (m, 2H).

[00153] Step H: DMAP (2.7 g, 22.3 mmol) and Boc₂0 (24.3 g, 1 1 1.5 mmol) were added to a solution of (4a'5,9a'J?)-2-amino-7'-bromo-l',4',4a^,,9a'-tetrahydro-5H-spiro[thiazole-4,9'- xanthen]-2'(3'H)-one (8.2 g, 22.3 mmol) in DCM (100 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed. The residue was purified by column chromatography on silica gel (hexanes:EtOAc, 20: 1 to 10: 1) to give a solid (8.0 g, 63.3% yield). 1H NMR (400MHz, CDC1₃) δ 7.65 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 2.4, 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.45-4.39 (m, 1 H), 3.72 (dd, J = 12, 76.8 Hz, 2H), 2.49-2.32 (m, 3H), 2.18 -2.12 (m, 1 H), 1.93 -1.89 (m, 1H), 1.56 (s, 18 H), 1.38 -1.24 (m, 2H).

[00154] Step I: Ammonium acetate (15.9 g, 206 mmol) was added to a solution of the product of Step H (7.3 g, 12.9 mmol) in MeOH (100 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (1.3 g, 20.6 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with DCM (3 X 200 mL). The solvent was removed under reduced pressure to give a crude product (7.0 g) that was used without further purification.

[00155] Step J: 2,2-Dimethyl-propionyl chloride (1.8 g, 14.8 mmol) was added dropwise at 0°C to a solution of the product of Step I (7.0 g, crude) and Et₃N (3.7 g, 37.0 mmol) in DCM (100 mL). The mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the mixture and extracted with DCM (3 X 50 mL). The solvent was removed, and the residue was purified by column chromatography on silica gel (10% ethyl acetate in petroleum ether) to give a solid (4.0 g, two diastereoisomers = 7:2).

[00156] Step K: A solution of the product of Step J (500 mg, 0.9 mmol) in 4N HCl/MeOH (40 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give N-((4a'S,9a'i?)-2-amino-7'-bromo-r,2',3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (400 mg, two diastereoisomers = 7:2) as a solid.

[00157] Step L: To a solution of -((43^,93\Κ)-2^ΐηο-7'^^ο-1 2\3^4',43',9^- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (250 mg, 0.55 mmol) in DMAc were added Zn(CN)₂ (45 mg, 0.39 mmol), dppf (60 mg, 0.1 mmol), Zn(CHO)₂-2H₂0 (45 mg, 0.2 mmol) and Pd/C (25 mg). The reaction was stirred at 140°C for 24 hours. The solid was filtered off, and the crude product was purified by pre-HPLC to give N-((2'S,4R 'S,9a'R)-2- amino-7'-cyano-r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (29.6 mg) and N-((2^,i?,4i?,4a ,9a'J?)-2-amino-7^,-cyano-l',2',3',4^,,4a',9a^,-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (1 1.5 mg) as a solid.

[00158] N-((2'S,4i?,4a'S,9a'/?)-2-Amino-7^,-cyano-l',2^,,3',4',4a',9a^,-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: Ή NMR (400MHz, CDC1₃) δ 7.92 (d, J = 1.6 Hz, 1H), 7.43 (dd, J = 2.0, 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.51 (d, J = 8.4 Hz, 1H), 4.14-4.08 (m, 1H), 3.98 -3.91 (m, 1H), 3.76 (dd, J = 12.0, 30.4 Hz, 2H), 2.32-2.26 (m, 1H), 2.07-2.01 (m, 2H), 1.89-1.82 (m, 1H), 1.68-1.55 (m, 1H), 1.42-1.20 (m, 2H), 1.18 (s, 9H); LCMS (ESI): RT = 1.033 min, m/z: 399.0 [M+H+], method=0-60AB/2 min.lcm.

[00159] N-((2'i?,4i?,4a'S,9a^,i?)-2-Amino-7^,-cyano-l',2',3',4^,,4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CDC1₃) δ 7.90 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 2.0, 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 4.27-4.18 (m, 1H), 3.78 -3.54 (m, 3H), 2.37-2.27 (m, 2H), 1.89-1.75 (m, 3H), 1.55-1.46 (m, 1H), 1.20 (s, 9H); LCMS (ESI): RT = 2.812 min, m/z: 399.2 [M+H+], method=0-60AB/7 min.lcm.

Exam le 21

N-((2 ^/?^a'^9a'j?V2-amino-7'-isopropyl-l 2 3\4 4a 9a'-hexahvdro-5H-spirorthiazole-4.9'- xanthen]-2'-yl)pivalamide

N-((2 4flA.W.9aW-2-amino-7'^

xanthen] -2'-vDpivalamide

[00160] Step A: Pd(PPh₃)₂Cl₂ (84 mg, 0.13 mmol) and Na₂C0₃ (318 mg, 3.0 mmol) were added to a solution of tert-butyl ((4a'5',9a'i?)-7'-bromo-2'-pivalamido-l',2^,,3',4',4a^,,9a'-hexahydro- 5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (350 mg, 0.6 mmol), 2-isopropenyl-4,4,5,5- tetramethyl-[l ,3,2]dioxaborolane (218 mg, 1.3 mmol) in dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 80°C under N₂ for 4 hours. The reaction mixture was dilute with water (10 mL), extracted with DCM (3 X 30 mL), and the combined extracts were dried over Na₂S0₄, filtered, and concentrated to afford the crude product, which was purified by column chromatography on silica gel (eluent: hexanes/EtOAc, 10: 1 to 2:1) to give r/-butyl ((4a ,9a'i?)-2'-pivalamido-7'-(prop-l-en-2-yl)-l 2^3^4^4a 9a'-hexahydro-5H-spiro[thiazole- 4,9'-xanthen]-2-yl)carbamate (250 mg, 77.2%, two diastereoisomers ratio = 3:1) as a solid.

[00161] Step B: 10% Pd/C (50 mg) was added to a solution of rt-butyl ((4a ,9a'i?)-2'- pivalamido-7'-( rop-l -en-2-yl)-r,2^,,3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9^,-xanthen]-2- yl)carbamate (250 mg, 0.49 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under H₂ atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give ter/-butyl ((4a'S,9a^,^)-7'-isopropyl-2'-pivalamido-l',2^,,3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (200 mg, 80.0%, two diastereoisomers ratio = 3 : 1 ) as a solid.

[00162] Step C: A solution of tert-butyl ((4a'S,9a'/?)-7^,-isopropyl-2'-pivalamido- r,2',3',4^,,4a',9a^,-hexahydro-5H-spiro[thiazole-4,9^,-xanthen]-2-yl)carbamate (200 mg, 0.39 mmol) in 4N HCl/MeOH (10 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC to give N-((2 ,4i^,4a ,9a^, ^)-2-amino-7'-isopropyl-1^2^3^4^4a 9a'-hexahydro-5H-spiro[thiazole- 4,9'-xanthen]-2'-yl)pivalamide (34.4 mg) and N-((2'/?,4 ?,4a'S,9a'^)-2-amino-7'-isopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (14.5 mg) as a solid.

[00163] N-((2'S,4i?,4a'S,9a'i?)-2-Amino-7'-isopropyl-l',2',3',4',4a',9a^,-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.36 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 1.6, 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.12-3.77 (m, 4H), 2.89 -2.82 (m, 1H), 2.39-1.40 (m, 7H), 1.20-1.13 (m, 15H); LCMS (ESI): RT = 1.150 min, m/z 416.1 [M+H+], method=0-60AB_2 min-E.M.

[00164] N-((2'i?,4^,4a'S,9a'i?)-2-Amino-7^,-isopropyl-l',2',3^,,4^,,4a^,,9a'-hexahydro-5H- spiro[thiazole-4,9^,-xanthen]-2'-yl)pivalamide: Ή NMR (400MHz, CD₃OD) δ 7.36 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 1.6, 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.02-3.83 (m, 4H), 2.89 -2.82 (m, 1H), 2.28-2.09 (m, 3H), 1.98-1.85 (m, 1H), 1.69-1.22 (m, 3H), 1.20-1.13 (m, 15H); LCMS (ESI): RT = 1.219 min, m/z 416.1 [M+H+], method=0-60AB_2 min-E.M. Example 22

N- 2 .4a .9a^,/?)-2-amino-7'-ethyl-l 2 3\4\4a 9a'-hexahvdro-5H-spirorthiazole-4.9'-xanto

2'-yl)pivalamide

.V-(f2 4aW.9a',¾V2-aiMno-7'-^^

2'-yl pivalamide

[00165] Step A: Pd(PPh₃)₂Cl₂ (116 mg, 0.17 mmol) and Na₂C0₃ (350 mg, 3.3 mmol) were added to a solution of tert-butyl ((4a'5',9a'^)-7'-bromo-2'-pivalamido-r,2^,,3^,,4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (600 mg, 1.1 mmol), potassium vinyl trifluoroborate (221 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 60°C under N₂ for 2 hours. The reaction mixture was dilute with water (10 mL), extracted with DCM (3 X 30 mL), and the combined extracts were dried over Na₂S0₄, filtered, and concentrated to afford the crude product, which was purified by column chromatography on silica gel (eluent: hexanes/EtOAc, 10:1 to 2:1) to give tert-butyl ((4a'S,9a'i?)-2'-pivalamido-7'- vinyl-r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (300 mg, 55.7%, two diastereoisomers ratio = 3:1) as a solid.

[00166] Step B: 10% Pd/C (50 mg) was added to a solution of rt-butyl ((4a'S,9a'i?)-2'- pivalamido-7'-vinyl- ,2^,,3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (250 mg, 0.49 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under H₂ atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give rt-butyl ((4a ,9a^,^)-7'-ethyl-2'-pivalamido-1^2 3^4',4a',9a'-hexahydro-5H-spiro[ιhiazole-4,9'- xanthen]-2-yl)carbamate (170 mg, 68.0%, two diastereoisomers ratio = 3:1) as a solid.

[00167] Step C: A solution of rt-butyl ((4a ,9a'^)-7'-ethyl-2'-pivalamido- l',2',3',4^,,4a',9a^,-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (170 mg, 0.34 mmol) in 4N HCl/MeOH (10 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC to give N-((2 ,4a ,9a^)-2-amino-7^,-ethyl-l',2^,,3',4^,,4a',9a^,-hexahydro-5H-spiro[thiazole-4,9'- xanthen]-2'-yl)pivalamide (33.9 mg) and N-((2^,i?,4a'S,9a^,i?)-2-amino-7'-ethyl-r,2',3^,,4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide (13.6 mg).

[00168] N-((2 ,4a'5,9a^)-2-Amino-7'-ethyl-l',2^,,3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.36 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 1.6, 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.07-3.79 (m, 4H), 2.63-2.57 (m, 2H), 2.32-2..13 (m, 3H), 1.99-1.90 (m, 1H), 1.73-1.62 (m, 1H), 1.53-1.27 (m, 2H), 1.20-1.15 (m, 12H); LCMS (ESI): RT = 1.108 min, m/z 402.1 [M+H+], method = 0-60AB_2min_ELSD.

[00169] N-((2'/?,4a ,9a'i?)-2-Amino-7'-ethyl- 1 ^,,2^,,3^,,4',4a',9a^,-hexahydro-5 - spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.35 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 1.6, 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.13-3.76 (m, 4H), 2.63 -2.57 (m, 2H), 2.41-1.99 (m, 4H), 1.83-1.45 (m, 3H), 1.20-1.15 (m, 12H); LCMS (ESI): RT = 1.165 min, m/z 402.1 [M+H+], method = 0-60AB_2min_ELSD.

Example 23

N-((2 .4a'S,9a^,i?)-2-amino-7^,-cvclopropyl-l'.2'.3^,.4'.4a'.9a'-hexahvdro-5H-spiro[thiazole-4.9'- xanthen]-2'-yl)pivalamide

N-((2^,4a'S.9a'i?)-2-amino-7'-cvclopropyl-l'.2^,.3'.4'.4a'.9a'-hexahvdro-5H-spiro[thiazole-4,9'- xanthen1-2'-yl)pivalamide

[00170] Step A: Potassium cyclopropyl-l-trifluoroborate (4.0 g, 26.9 mmol), Pd(OAc)₂ (605 mg, 2.7 mmol), RuPhos (2.5 g, 5.4 mmol) and K₃P0₄ (11.4 g, 54.0 mmol) were added to a solution of (4a'S,9a'i?)-7'-bromo-9'-methylene-l',3',4',4a',9',9a^,-hexahydrospiro[[l,3]dioxolane- 2,2'-xanthene] (6.0 g, 17.9 mmol) in toluene (60 mL) and H₂0 (6 mL). The mixture was sparged with N₂ for 2 minutes and then heated to 110°C for 24 hours with stirring. The mixture was poured into water, and extracted with EtOAc (3 X 50 mL). The combined organic layers were dried and concentrated to afford the crude product, which was purified by column on silica gel (PE: EtOAc = 30:1) to give (4a'S,9a'i?)-7^,-cyclopropyl-9^,-methylene-l^,,3',4',4a',9^,,9a'- hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (3.8 g, 71.7% yield) as a solid. 1H NMR (400 MHz, CDC1₃) δ 7.28 (d, J - 2.0 Hz, 1H), 6.90 (dd, J = 8.4, 2.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.50 (d, J = 2.4 Hz, 1H), 4.83 (d, J = 2.4 Ηζ,ΙΗ), 4.03-3.95 (m, 4H), 3.72-3.63 (m, 1H), 2.62- 2.53 (m, 1H), 2.38-2.13 (m, 2H), 1.95-1.80 (m, 3H), 1.70-1.62 (m, 2H), 0.90-0.83 (m, 2H), 0.64-0.58 (m, 2H).

[00171] Step B: A solution of iodine (1.0 g, 4.0 mmol) in EtOAc (15 mL) was added dropwise to a suspension of AgSCN (840 mg ,5.1 mmol) and (4a'S,9a'i?)-7'-cyclopropyl-9'- methylene-r,3',4^,,4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (1.0 g, 3.4 mmol) in acetonitrile (15 mL) and EtOAc(15 mL) at 0°C. After 3 hours, the reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (50 mL), and NH₄OH (15 mL, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated NaHC0₃, and the aqueous layer was extracted with EtOAc (3 X 50 mL). The combined organic layers were dried and concentrated to afford a solid (0.9 g, crude) that was used without further purification.

[00172] Step C: A solution of the crude product of Step (900 mg) in 3N HC1 (25 mL) and THF (50 mL) was heated at 60°C for 16 hours. The mixture was basified with saturated NaHC0₃ until the pH was greater than 10, and the mixture was extracted with EtOAc (3 X 100 mL). The combined organic layers were dried, concentrated, and purified by trituration with PE to give (4a'S,9a'^)-2-amino-7'-cyclopropyl- 1 ',4',4a',9a'-tetrahydro-5H-spiro[thiazole-4,9'- xanthen]-2'(3'H)-one (750 mg, crude, 82% purity) as a solid that was used without further purification. LCMS (ESI): RT = 2.944 minutes, m/z 328.9 [Μ+Η+], method=0-60AB/7 min.lcm.

[00173] Step D: DMAP (279 mg, 2.3 mmol) and Boc₂0 (1.5 g, 6.9 mmol) were added to a solution of (4a'5',9a^,i?)-2-amino-7'-cyclopropyl- 1 ',4',4a',9a'-tetrahydro-5H-spiro[thiazole-4,9'- xanthen]-2'(3'H)-one (750 mg, crude) in DCM (10 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 to 10: 1) to give tert-butyl ((4a'S,9a'i?)-7^*-cyclopropyl-2'-oxo-l',2^,,3',4^,,4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]- 2-yl)carbamate (750 mg, crude) as a solid. LCMS (ESI): RT = 3.741 minutes, m/z 429.1 [Μ+Η+], method=10-80AB/7 min.lcm.

[00174] Step E: Ammonium acetate (2.1 g, 28.0 mmol) was added to a solution of tert- butyl ((4a ,9a'i?)-7'-cyclopropyl-2'-oxo-l',2',3',4',4a',9a^,-hexahydro-5H-spiro[thiazole-4,9'- xanthen]-2-yl)carbamate (750 mg, crude) in MeOH (10 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (180 mg, 2.8 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHC03 and extracted with DCM (3 X 50 mL). The solvent was removed under reduced pressure to give crude tert-butyl ((4a'S,9a'^)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (530 mg, two diastereomers = 1 :2) that was used without further purification. LCMS (ESI): RT = 3.606, 3.71 1 minutes, m/z 430.1 [M+H+], method=0-60AB/7 min.lcm.

[00175] Step F: 2,2-Dimethyl-propionyl chloride (180 mg, 1.5 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4a'5',9a'i?)-2^,-amino-7'-cyclopropyl-l',2',3',4',4a',9a'- hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (530 mg, crude) and Et₃N (370 mg, 3.7 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the mixture, and extracted with DCM (3 X 20 mL). The solvent was removed to give tert-butyl ((4a'iS',9a^,iv^,)-7'-cyclopropyl-2'-pivalamido- ,2^,,3^,,4',4a',9a'-hexahydro- 5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (350 mg, crude, two diastereomers = 1 :2) as a solid that was used without further purification.

[00176] Step G: A solution of tert-butyl ((4a'S,9a'i?)-7'-cyclopropyl-2'-pivalamido- ,2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2-yl)carbamate (350 mg, crude) in 4N HCl/MeOH (40 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC (HCl) to give N-((2 ,4a ,9a ?)-2-amino-7'-cyclopropyl-1^2^

xanthen]-2'-yl)pivalamide (43.3 mg) and N-((2'7?,4a'5',9a'i?)-2-amino-7'-cyclopropyl- l',2',3',4^,,4a^,,9a'-hexahydro-5H-spiro[thiazole-4,9^,-xanthen]-2'-yl)pivalamide (33.6 mg).

[00177] N-((2'S,4a'S,9a'i?)-2-amino-7^,-cyclopropyl-l^,,2^,,3',4^,,4a^,,9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: Ή NMR (400MHz, CD₃OD) δ 7.28 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 2.4, 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.04-3.75 (m, 4H), 2.41-2.20 (m, 3H), 2.00-1.83 (m, 2H), 1.73-1.61 (m, 1H), 1.52-1.36 (m, 1H), 1.34-1.28 (m, 1H), 1.20 (s, 9H), 0.91-0.89 (m, 2H), 0.61-0.53 (m, 2H). LCMS (ESI): RT = 0.852 minutes, m/z 414.1 [M+H+], method=10-80AB_2 min.lcm.

[00178] N-((2'/?,4a'5,9a'i?)-2-amino-7^,-cyclopropyl-r,2^,,3',4',4a',9a'-hexahydro-5H- spiro[thiazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.29 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 2.0, 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.10-3.75 (m, 4H), 2.41-1.65 (m, 7H), 1.49-1.40 (m, 1H), 1.22 (s, 9H), 0.91-0.88 (m, 2H), 0.62-0.56 (m, 2H). LCMS (ESI): RT = 0.907 minutes, m/z 414.1 [M+H+], method=10-80AB_2 min.lcm.

Example 24

N-((2 .4i?^a .9a'i?)-2-amino-7'-cvclopropyl-l'.2^,.3'.4'.4a'.9a'-hexahvdro-5H-spiro oxazole-4,9'- xanthen]-2'-yl)pivalamide

N-r(2'j?,4^.4a .9a'j?V2-amino-7'-cvclopropyl-l 2'.3^,.4'.4a',9a'-hexahvdro-5H-spiro[oxazole-

4,9'-xanthen]-2'-yl pivalamide

[00179] Step A: A solution of iodine (1.0 g, 4.0 mmol) in EtOAc (30 mL) was added dropwise to a suspension of AgOCN (705 mg, 4.7 mmol ) and (4a'S,9a'7?)-7'-cyclopropyl-9'- methylene-r,3',4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (1.0 g, 3.4 mmol) in acetonitrile (15 mL) and EtOAc (15 mL) at 0°C. After 3 hours, the reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (50 mL), and NH₄OH (10 ml, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and saturated NaHC0₃, and the aqueous layer was extracted with EtOAc (3 X 50 mL). The combined organic layers were dried and concentrated to give a solid (1.0 g, crude, mixture of two diastereomers) that was used without further purification.

[00180] Step B: A solution of the product of Step A (1.0 g, crude) in 3N HC1 (30 mL), acetone (80 mL) and THF (10 mL) was heated at 60°C for 16 hours. The mixture was basified with saturated NaHC0₃ until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 50mL). The combined organic layers were dried, concentrated, and purified by trituration with PE to give (4a'5',9a^,i?)-2-amino-7^,-cyclopropyl-r,4^,,4a',9a^,-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (850 mg, crude, mixture of two diastereomers) as a solid that was used without further purification.

[00181] Step C: DMAP (330 mg, 2.7 mmol) and Boc₂0 (1.8 g, 8.16 mmol) were added to a solution of (4a ,9a'/?)-2-amino-7'-cyclopropyl-l',4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (850 mg, crude) in DCM (100 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel (eluting with 5%-10% ethyl acetate in petroleum ether) to give tert-butyl ((4S,4a'S,9a'R)-7'-cyclopropyl-2'-oxo-l',2',3',4',4a',9a^,-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (270 mg, crude) and iV-((2'i?,4i?,4a'S,9a'i?)-2-amino- 7'-cyclopropyl- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (560 mg, crude) as a solid. LCMS (ESI): RT = 2.679, 2.720 minutes, m/z 413.1 [M+H+], method=10- 80AB/7 min.lcm.

[00182] Step D: Ammonium acetate (772 mg, 10 mmol) to a solution of tert-butyl ((45,4a^,5,9a^,i^)-7'-cyclopropyl-2'-oxo-l',2^,,3',4^,,4a',9a^,-hexahydro-5H-spiro[oxazole-4,9^,- xanthen]-2-yl)carbamate (270 mg, crude) in MeOH (10 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (63 mg, 1.0 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHC0₃ and extracted with DCM (3 X 50 mL). The solvent was removed under reduced pressure to give crude tert-butyl ((4S,4a ,9a ?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (250 mg, mixture of two diastereomers) that was used without further purification. [00183] Step E: 2,2-Dimethyl-propionyl chloride (1 10 mg, 0.9 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4S,4a ,9a'i?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (250 mg, 0.6, crude) and Et₃N (184 mg, 1.8 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the mixture, and extracted with DCM (3 X 20 mL). The solvent was removed to give tert-butyl ((4S,4a'S,9a'i?)-7'-cyclopropyl-2'-pivalamido- l',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (250 mg, mixture of two diastereomers) as a solid that was used without further purification.

[00184] Step F: A solution of fert-butyl ((4S,4a^,S,9a'_JR)-7'-cyclopropyl-2'-pivalamido- r,2^,,3^,,4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (250 mg, crude) in 4N HCl/MeOH (20 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC (HCl) to give N-((2'S,4 ?,4a'S,9a'_JR)-2-amino-7'-cyclopropyl-l',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'- xanthen]-2'-yl)pivalamide (44.6 mg) and N-((27?,4J?,4a ,9a7?)-2-amino-7'-cyclopropyl- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (11.5 mg).

[00185] N-((2'S,4/?,4a'S,9a'i?)-2-Amino-7^,-cyclopropyl-l',2',3',4^,,4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.05 (d, J - 2.4 Hz, 1H), 6.87 (dd, J = 2.4, 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.56 (d, J = 8.8 Hz, 1H), 3.98 (d, J = 8.8 Hz, 1H), 3.82-3.80 (m, 2H), 2.27-2.23 (m, 1H), 1.95-1.84 (m, 4H), 1.68-1.61 (m, 1H), 1.53-1.41 (m, 1H), 1.36-1.25 (m, 1H), 1.18 (s, 9H), 0.91-0.86 (m, 2H), 0.62-0.53 (m, 2H); LCMS (ESI): RT = 0.858 minutes, m/z 398.1 [M+H+], method=10-80AB_2 min.lcm.

[00186] N-((2'i?,4i?,4a^,S,9a'i?)-2-Amino-7'-cyclopropyl-l',2',3^,,4^,,4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.05 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 2.4, 8.8 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 8.8 Hz, 1H), 4.15- 4.14 (m, 2H), 3.96 (d, J = 8.8 Hz, 1H), 3.90-3.86 (m, 1H), 2.17-1.83 (m, 5H), 1.73-1.71 (m, 2H), 1.52-1.41 (m, 1H), 1.18 (s, 9H), 0.90-0.86 (m, 2H), 0.61-0.53 (m, 2H); LCMS (ESI): RT = 0.993 minutes, m/z 398.0 [M+H+], method=10-80AB_2 min.lcm. Exam le 25

^-( ^.4 .4^,9Ε'^)-2- ίηο-7'-ον€ΐορΓορν1-1 2',3',4'.4α'.9α'-1ΐ6Χ3ΐιν(ΐΓθ-5^5ρίΓθ[ο ζοΐ6-4.9'- xanthen1-2'-vnpivalamide

N-((2'i^ S.4a .9a'i^)-2-amino-7'-cvclopropyl-1 2^3 4 4a 9a^,-hexahvdro-5H-spiro[oxazole-4.9'- xanthenl -2'-yl)pivalamide

[00187] Step A: to a solution of tert-butyl ((45,4a'_iS,9a'i?)-7'-cyclopropyl-2'-oxo- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (560 mg, crude) in MeOH (15 mL) was added ammonium acetate (1.7 g, 22 mmol). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (140 mg, 2.2 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHC0₃ and extracted with DCM (3 X 50 mL). The solvent was removed under reduced pressure to give crude tert-butyl ((4S,4a'5',9a'/?)-2'-amino-7'- cyclopropyl- 1 ',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (480 mg, two diastereomers = 1 :2.5) that was used without further purification. LCMS (ESI): RT = 3.309, 3.342 minutes, m/z 414.1 [Μ+Η+], method=0-60AB/7 min.lcm.

[00188] Step B: 2,2-Dimethyl-propionyl chloride (220 mg, 1.8 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4S,4a'S,9a ?)-2'-amino-7'-cyclopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (480 mg, crude) and Et₃N (350 mg, 3.5 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the mixture, and extracted with DCM (3 X 50 mL). The solvent was removed to give tert-butyl ((4S,4a'S,9a7?)-7'-cyclopropyl-2'-pivalamido- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (450 mg, two diastereomers = 1 :2.5) as a solid that was used without further purification.

[00189] Step C: A solution of rt-butyl ((45',4a'S^,,9a'i?)-7'-cyclopropyl-2'-pivalamido- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (450 mg, crude) in 4N HCl/MeOH (20 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC (HCl) to give N-((2 ,45,4a ,9a'i?)-2-amino-7'-cyclopropyl-l',2',3',4',4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'- xanthen]-2'-yl)pivalamide (67.7 mg) and N-((2'#,4S,4a ,9a7?)-2-amino-7'-cyclopropyl- 1 '^'^'^'^a'^a'-hexahydro-SH-spirofoxazole^^'-xanthenl^'-y pivalamide (27.4 mg). [00190] ^-(( 'S^S^a'S^a'^^-Amino-T'-cyclopropyl-r^'^'^'^a'^a'-hexahydro-SH- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalaniide: 1H NMR (400MHz, CD₃OD) δ 6.99 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 2.0, 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.54 (d, J = 8.8 Hz, 1H), 4.41 (d, J = 8.8 Hz, 1H), 3.91-3.85 (m, 2H), 2.27-2.22 (m, 1H), 1.94-1.83 (m, 4H), 1.68-1.55 (m, 1H), 1.52-1.30 (m, 2H), 1.20 (s, 9H), 0.89-0.85 (m, 2H), 0.60-0.52 (m, 2H); LCMS (ESI): RT = 0.851 minutes, m/z 398.1 [M+H+], method=10-80AB_2 min.lcm.

[00191] N-((2'i?,4S,4a'S,9a'i?)-2-Amino-7'-cyclopropyl-l',2',3',4^,,4a^,,9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.16 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 2.0, 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.04 (d, J = 8.8 Hz, 1H), 4.78 (d, J = 8.8 Hz, 1H), 4.12-4.10 (m, 1H), 3.84-3.83 (m, 1H), 2.21-2.00 (m, 4H), 1.90-1.62 (m, 3H), 1.45-1.44 (m, 1H), 1.19 (s, 9H), 0.92-0.86 (m, 2H), 0.62-0.56 (m, 2H); LCMS (ESI): RT = 0.897 minutes, m/z 398.1 [M+H+], method=10-80AB_2 min.lcm.

Example 26

N-f^a'S.ga'^^^-amino-l'^' '^'^a'^a'-hexahvdro-SH-spiroroxa ole^.g'-xanthenl^'- vDpivalamide

[00192] Step A: A solution of iodine (9.2 g, 36 mmol) in EtOAc (120 mL) was added dropwise to a suspension of AgOCN (6.3 g, 42 mmol) and (4a ,9a'i?)-7'-bromo-9'-methylene- r,3^,,4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthene] (10 g, 30 mmol) in acetonitrile (60 mL) and EtOAc (60 mL) at 0°C. After 3 hours, the reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (400 mL), and NH₄OH (50 mL, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and saturated NaHC0₃, and the aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organic layers were dried and concentrated to afford the crude product, which was purified by trituration with PE to give a solid (11.0 g, mixture of two diastereomers).

[00193] Step B: A solution of the product of Step A (11.0 g, 27 mmol) in 3N HC1 (150 mL), acetone (150 mL) was heated at 60°C for 16 hours. The mixture was basified with NaOH until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 500 mL). The combined organic layers were dried, concentrated, and purified by trituration with PE to give (4a ,9a^)-2-amino-7'-bromo-1^4^4a^9a'-tetrahydro-^^

(8.5 g, mixture of two diastereomers) as a solid.

[00194] Step C: DMAP (1.4 g, 11.4 mmol) and Boc₂0 (5.0 g, 22.8 mmol) was added to a solution of (4a^,S,9a'i?)-2-amino-7'-bromo- ,4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (4.0 g, 11.4 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel (eluting with 30%-50% ethyl acetate in petroleum ether) to give tert-butyl ((4a'S,9a^)-7'-bromo-2^,-oxo-r,2',3^,,4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (2.8 g, 54.0% yield) as a solid. LCMS (ESI): RT = 1.012 minutes, m/z 395.0(M+H+-56), method=10-80AB/2 min.

[00195] Step D: Ammonium acetate (2.6 g, 33.3 mmol) to a solution of tert-butyl ((4a'5,9a^, _J/?)-7'-bromo-2'-oxo-l',2',3',4^,,4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2- yl)carbamate (1.0 g, 2.2 mmol) in MeOH (50 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (210 mg, 3.33 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with DCM (3 X 50 mL). The solvent was removed under reduced pressure to give tert-butyl ((4a'S,9a'i?)-2'-amino-7'-bromo-l',2',3',4',4a^,,9a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (1.0 g, crude) that was used without further purification.

[00196] Step E: 2,2-Dimethyl-propionyl chloride (400 mg, 3.3 mmol) was added dropwise at 0°C to a solution of tert-butyl ((4a'5,9a'J?)-2^,-amino-7^,-bromo-l',2',3',4^,,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (1.0 g, crude) and Et₃N (670 mg, 6.6 mmol) in DCM (50 mL). The mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the mixture, and extracted with DCM (3 X 50 mL). The solvent was removed, and the residue was purified by column chromatography on silica gel (30% ethyl acetate in petroleum ether) to give tert-butyl ((4a'S,9a'i?)-7'-bromo-2'-pivalamido-l',2^,,3',4',4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (450 mg, two diastereomers = 74.4:25.5) as a solid. LCMS (ESI): RT = 3.243, 3.355 minutes, m/z 536.2[M+H+], method=10- 80AB/7 min.

[00197] Step F: 10% Pd/C (50 mg) was added to a solution of tert-butyl ((4a'5,9a'i?)-7'- bromo-2^,-pivalamido-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2- yl)carbamate (250 mg, 0.47 mmol) in MeOH (8 mL). The mixture was stirred at room temperature under H₂ atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give tert-butyl ((4S,4a'S,9a'i?)-2'-pivalamido-l',2',3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (200 mg, 89% yield). LCMS (ESI): RT = 0.999 minutes, m/z 458.2 [M+H+], method=10-80AB/2 min.

[00198] Step G: A solution of rt-butyl ((4S,4a^,5,9a'/?)-2^,-pivalamido-l',2',3^,,4^,,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (140 mg, 0.3 mmol) in 4N HCl/MeOH (5 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give the crude product, which was purified by pre-HPLC to give V- ((4a'S,9a'^)-2-amino-l',2',3',4^,,4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9^,-xanthen]-2'- yl)pivalamide (19.0 mg). Ή NMR (400MHz, CD₃OD) δ 7.49 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.1 1 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 5.1 1-5.03 (m, 2H), 3.94-3.88 (m, 2H), 2.39-2.35 (m, 1H), 2.19-2.01 (m, 3H), 1.77-1.74 (m, 1H), 1.57-1.54 (m, 1H), 1.38-1.35 (m, 1H), 1.23 (s, 9H); LCMS (ESI): RT = 0.765 minutes, m/z 358.1 [M+H+], method=10- 80AB/2 min ELSD.

Example 27

N-((2 .4a'S.9a'i?)-2-amino-7'-cvano-l'.2'.3'.4'.4a'.9a'-hexahvdro-5H-spiroroxazole-4.9'-xanthen1-

2'-yl)pivalamide

N-(f2'/?_>4a'S.9a'^V2-amino-7'-cvano-l'.2'.3'.4',4a'.9a'-hexahvdro-5H-spiro[oxazole-4.9'- xanthen]-2'-yl)pivalamide

[00199] Step A: A solution of /ert-butyl ((4a'S,9a' ?)-7^,-bromo-2'-pivalamido- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2-yl)carbamate (2.0 g, 3.7 mmol) in 4N HCl/MeOH (50 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to give N-((4a'iS',9a^,J?)-2-amino-7'-bromo- ,2',3',4^,,4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (1.6 g, mixture of two diastereomers) as a solid.

[00200] Step B: Zn(CN)₂ (45 mg, 0.39 mmol), dppf (60 mg, 0.1 mmol), Zn(CHO)₂-2H₂0 (45 mg, 0.2 mmol) and Pd/C (25 mg) were added to a solution of N-((4a'5',9a' ?)-2-amino-7'- bromo-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9^,-xanthen]-2'-yl)pivalamide (350 mg, crude) in DM Ac. The reaction was stirred at 140°C for 24 hours. The solid was filtered off, and the crude product was purified by pre-HPLC (base) to give iV-((2^,S,4a'S,9a'i?)-2-amino-7'-cyano- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9^,-xanthen]-2'-yl)pivalamide (38.4 mg) and N- ((2'J?,4a ,9a'i?)-2-amino-7'-cyano-1^2^3^4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]- 2'-yl)pivalamide (2.8 mg). [00201] N-((2 ,4a'S,9a'i?)-2-Amino-7^,-cyano-l^,,2^,,3^,,4^,,4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.64 (d, J = 2.0Hz, 1H), 7.50 (d, J = 2.0, 8.4Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.56 (d, J = 9.2Hz, 1H), 4.43 (d, J = 9.2Hz, 1H), 4.07-3.97 (m, 1H), 3.88-3.82 (m, 1H), 2.30-2.26 (m, 1H), 1.95-1.82 (m, 3H), 1.66- 1.61 (m, 1H), 1.47-1.30 (m, 2H), 1.28 (s, 9H). LCMS (ESI): RT = 0.792 minutes, m/z 383.1 [M+H+], method=10-80AB/2 min ELSD.

[00202] N-((2^,i?,4a^,S,9a'i?)-2-Amino-7'-cyano-l',2^,,3',4^,,4a',9a^,-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2^,-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.66 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.59 (d, J = 9.6 Hz, 1H), 4.47 (d, J = 9.6 Hz, 1H), 4.06 (m, 1H), 3.87 (m, 1H), 2.31 (m, 1H), 1.90 (m, 3H), 1.67 (m, 1H), 1.48 (m, 2H), 1.29 (s, 9H). LCMS (ESI): RT = 0.789 minutes, m/z 383.1 [M+H+], method=10-80AB/2 min ELSD.

Example 28

N-((2'S.4a'S.9a'7?V2-amino-7'-isopropyl-l',2'.3',4'.4a^,.9a'-hexahvdro-5H-spiroroxazole-4.9'- xanthen]-2'-yl)pivalamide

N-((2'i?.4a .9a'^V2-amino-7'-isopropyl-l'.2'.3^,.4'.4a'.9a'-hexahvdro-5H-spiroroxazole-4.9'- xanthen] -2'- vDpivalamide

[00203] Step A: Pd(PPh₃)₂Cl₂ (53 mg, 0.08 mmol) and Na₂C0₃ (160 mg, 1.5 mmol) were added to a solution of N-((4a'S,9a'i?)-2-amino-7^,-bromo-l^,,2',3',4',4a',9a^,-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (235 mg, 0.5 mmol), 4,4,5,5-tetramethyl-2-(prop- l-en-2-yl)-l,3,2-dioxaborolane (126 mg, 0.75 mmol) in dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 80°C under N₂ for 16 hours. The reaction mixture was dilute with water (10 mL), extracted with DCM (3 X 30 mL), and the combined extracts were dried over Na₂S0₄, filtered, and concentrated to afford N-((4a'S,9a' ?)-2-amino-7'-(prop-l-en-2-yl)- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, crude) that was used without further purification.

[00204] Step B: 10% Pd/C (50 mg) was added to a solution of N-((4a'5,9a'i?)-2-amino-7'- ( rop-l-en-2-yl)-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H₂ atmosphere for 6 hours. The catalyst was filtered off, and the filtrate was concentrated to give the crude product, which was purified by prep-HPLC (base) to give the desired product of N- ((2'S,4a^*S,9a'i?)-2-arnino-7^*-isopropyl-l^,,2',3',4',4a',9a^,-hexahydro-5H-spiro[oxazole-4,9'- xanthen]-2'-yl)pivalamide (16.8 mg) and N-((2'_J/?,4a'S,9a'/?)-2-amino-7'-isopropyl- 1 ',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (9.3 mg).

[00205] N-((2 ,4a'S,9a'J?)-2-Amino-7^,-isopropyl- 1 '^'^'^'^a'^a'-hexahydro-SH- spiro[oxazole-4,9^,-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.06 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.38 (d, J = 8.8 Hz, 1H), 3.89 (m, 2H), 2.83 (m, 1H), 2.24 (m, 1H), 1.88 (m, 3H), 1.79 (m, 3H), 1.31 (m, 3H), 1.28 (s, 12H); LCMS (ESI): RT - 0.954 minutes, m/z 400.1 [M+H+], method=10-80AB/2 min ELSD.

[00206] N-((2^,J?,4a ,9a' ?)-2-Amino-7'-isopropyl- 1 '^'^'^'^a'^a'-hexahydro-SH- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.06 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.53 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 4.08 (m, 2H), 3.96 (m, 1H), 2.84 (m, 1H), 2.06-1.51 (m, 8H), 1.19 (s, 12H), 1.15 (m, 4H); LCMS (ESI): RT = 1.001 minutes, m/z 400.1 [M+H+], method=10-80AB/2 min ELSD.

Example 29

N-i(2'i?.4a'S.9a'^)-2-amino-7'-cvclohexyl-l',2'.3'.4'.4a'.9a^,-hexahvdro-5H-spiroroxazole-4.9'- xanthen1-2'-yl)pivalamide

N-((2 ^a .9a'^V2-amino-7'-cvclohexyl-l'.2',3'.4',4a'.9a'-hexahvdro-5H-spiroroxazole-4,9'- xanthen]-2'-yl)pivalamide

[00207] Step A: Pd(PPh₃)₂Cl₂ (116 mg, 0.17 mmol ) and Na₂C0₃ (350 mg, 3.3 mmol) were added to a solution of N-((4a'S,9a^,^)-2-amino-7^,-bromo-l',2^,,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, 1.1 mmol), 2-(cyclohex-l-en-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (358 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 80°C under N₂ for 3 hours. The reaction mixture was dilute with water (10 mL), extracted with DCM (3 X 30 mL), and the combined extracts were dried over Na₂S0₄, filtered, and concentrated to afford N-((4a ,9a ?)-2-amino-7'-(cyclohex-l- en- 1 -yl)- 1 ',2',3 ',4^,,4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen] -2'-yl)pivalamide (600 mg, crude) that was used without further purification.

[00208] Step B: 10% Pd/C (50 mg) was added to a solution of N-((4a ,9a'i?)-2-amino-7'- (cyclohex- 1 -en- 1 -yl)- 1 ',2',3 ',4',4a',9a'-hexahydro-5H-spiro [oxazole-4,9'-xanthen] -2'- yl)pivalamide (600 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H₂ atmosphere for 6 hours. The catalyst was filtered off, and the filtrate was concentrated to give the crude product, which was purified by prep HPLC (base) to give N-((2'/?,4a'S,9a'i?)-2- amino-7'-cyclohexyl- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'- yl)pivalamide (11.0 mg) and N-((2 ,4a ,9a'i?)-2-amino-7'-cyclohexyl-l',2',3',4',4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (5.6 mg).

[00209] N-((2'i?,4a'S,9a\K)-2- Amino-7'-cyclohexyl- 1 ',2',3 ',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.42 (d, J =8.0 Hz, IH), 7.22 (s, IH), 7.18 (d, J =8.4 Hz, IH), 6.81 (d, J =8.4 Hz, IH), 5.05 (d, J =9.6 Hz, IH), 4.98 (d, J =10.0 Hz, IH), 3.85 (m, 2H), 2.54 (m, IH), 2.33 (m, IH), 2.12 (m, 2H), 2.03 (m, IH), 1.82 (m, 5H), 1.71 (m, 2H), 1.48 (m, 4H), 1.20 (s, 9H); LCMS (ESI): RT = 1.016 minutes, m/z 440.2[M+H+], method=10-80AB/2 min_ELSD.

[00210] N-((2'S,4a ,9a'i?)-2-Amino-7'-cyclohexyl-l^,,2',3^,,4^,,4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.23 (s, IH), 7.18 (d, J =8.8 Hz, IH), 6.81 (d, J =8.8 Hz, IH), 5.05 (d, J =9.6 Hz, IH), 4.14 (m, IH), 3.91 (m, 2H), 2.54 (m, IH), 2.33 (m, IH), 2.12 (m, 2H), 2.03 (m, IH), 1.82 (m, 5H), 1.71 (m, 2H), 1.48 (m, 4H), 1.20 (s, 9H); LCMS (ESI): RT = 1.062 minutes, m/z 440.2[M+H+], method=10-80AB/2 min ELSD.

Example 30

N-((2'i?.4a'S.9a'^V2-amino-7'-cvclopentyl-l'.2'.3'.4'.4a',9a'-hexahvdro-5H-spiroroxazole-4,9'- xanthen]-2'-yl)pivalamide

N-r(2 .4a^,i?.9a'^-2-amino-7'-cvclopenryl-l'.2'.3'.4'.4a'.9a'-hexahvdro-5H-spiroroxazole-4,9'- xanthen]-2'-yl)pivalamide

[00211] Step A: Pd(PPh₃)₂Cl₂ (116 mg, 0.17 mmol) and Na₂C0₃ (350 mg, 3.3 mmol) were added to a solution of N-((4a'5^,,9a'i?)-2-amino-7^,-bromo-l',2',3^,,4^,,4a',9a^,-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (500 mg, 1.1 mmol), 2-(cyclopent-l-en-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (330 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 80°C under N₂ for 3 hours. The reaction mixture was dilute with water (10 mL), extracted with DCM (3 X 30 mL), and the combined extracts were dried over Na₂S0₄, filtered, and concentrated to afford N-((4a ,9a7?)-2-amino-7'-(cyclopent-l- en-l-yl)-l 2',3',4^,,4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (600 mg, crude) that was used without further purification.

[00212] Step B: 10% Pd/C (50 mg) to a solution of N-((4a'S,9a'i?)-2-amino-7'-(cyclopent- 1 -en- 1 -yl)- 1 ^*,2',3 '^'^a'^a'-hexahydro-SH-spiro [oxazole-4,9'-xanthen] -2'-yl)pivalamide (600 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H₂ atmosphere for 6 hours. The catalyst was filtered off, and the filtrate was concentrated to give the crude product, which was purified by prep-HPLC (base) to give N-((2'i?,4a ,9a'i?)-2-amino- y'-cyclopentyl-r^^^^a'^a'-hexahydro-SH-spirofoxazole^^'-xanthenJ^'-y^pivalamide (60 mg), then separated by SFC to give N-((2'i?,4a'S,9a' ?)-2-amino-7'-cyclopentyl-l',2^,,3',4',4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (9.0 mg) and N-((2'S,4a'i?,9a'S)-2- amino-7'-cyclopentyl- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'- yl)pivalamide (25.0 mg).

[00213] N-((2^,4a'5,9a'i?)-2-Amino-7'-cyclopentyl-l',2^,,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.08 (s, IH), 7.03 (d, J =8.4 Hz, IH), 6.89 (d, J =8.4 Hz, IH), 4.50 (d, J =8.8 Hz, IH), 4.38 (d, J =8.8 Hz, IH), 3.88 (m, 2H), 2.97 (m, IH), 2.26 (m, IH), 2.01 (m, 2H), 1.84 (m, 5H), 1.74 (m, 6H), 1.48 (m, IH), 1.20 (s, 9H). LCMS (ESI): RT = 0.999 minutes, m/z 426.1 [M+H+], method=10-80AB/2 min ELSD.

[00214] N-((2'5,4a'i?,9a'S)-2-Amino-7'-cyclopentyl-l',2',3^,,4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9^*-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.09 (s, IH), 7.05 (d, J = 8.4 Hz, IH), 6.70 (d, J = 8.4 Hz, IH), 4.55 (d, J=8.8 Hz, IH), 4.42 (d, J=9.2 Hz, IH), 3.88 (m, 2H), 2.97 (m, IH), 2.26 (m, IH), 2.01 (m, 2H), 1.84 (m, 5H), 1.74 (m, 6H), 1.48 (m, IH), 1.20 (s, 9H). LCMS (ESI): RT = 1.001 minutes, m/z 426.1 [M+H+], method=10-80AB/2 min ELSD.

Example 31

N- 2'ig,4a .9a'i?)-2-amino-7^,-rtetrahvdro-2H-pyran-4-vn-l^,.2'.3'.4'.4a'.9a'-hexahvdro-5H- spiro[oxazole-4.9'-xanthen]-2'-yl)pivalamide

N-((2 .4a'^j?.9a'^-2-amino-7'- etrahvdro-2H-pyran-4-yl)-l'.2',3^,.4'.4a'.9a^,-hexahvdro-5H- spiro [oxazole-4,9'-xanthen] -2'-yl)pivalamide [00215] Step A: Pd(PPh₃)₂Cl₂ (116 mg, 0.17 mmol) and Na₂C0₃ (350 mg, 3.3 mmol) to a solution of N-((4a^, ₁S,9a'i^)-2-amino-7'-bromo-l ',2^,,3^,,4',4a',9a'-hexahydro-5H-spiΓo[oxazole-4,9^,- xanthen]-2'-yl)pivalamide (500 mg, 1.1 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (357 mg, 1.7 mmol) in dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 80°C under N₂ for 3 hours. The reaction mixture was dilute with water (10 mL), extracted with DCM (3 X 30 mL), and the combined extracts were dried over Na₂S0₄, filtered, and concentrated to afford N-((4a'S,9a'i?)-2-amino-7'-(3,6-dihydro-2H-pyran-4- yl)- ,2',3',4',4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (600 mg, crude) that was used without further purification.

[00216] Step B: 10% Pd/C (50 mg) was added to a solution of

(3,6-dihydro-2H-pyran-4-yl)-l^,,2^,,3^,,4',4a',9a^,-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'- yl)pivalamide (600 mg, crude) in MeOH (20 mL). The mixture was stirred at room temperature under H₂ atmosphere for 6 hours. The catalyst was filtered off, and the filtrate was concentrated to give the crude product, which was purified by prep-HPLC (base) to give N-((2' ?,4a'S,9a'i?)-2- amino-7'-(tetrahydro-2H-pyran-4-yl)- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'- xanthen]-2'-yl)pivalamide (40 mg), then separated by SFC to give N-((2'i?,4a^,S,9a'/?)-2-amino-7'- (tetrahydro-2H-pyran-4-yl)-l^,,2',3',4^,,4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'- yl)pivalamide (4.3 mg) and N-((2'S,4a'i?,9a^,S)-2-amino-7^,-(tetrahydro-2H-pyran-4-yl)- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (6.1 mg).

[00217] N-((2'/?,4a ,9a'i?)-2-Amino-7^,-(tetrahydro-2H-pyran-4-yl)-l',2^,,3^,,4^,,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: Ή NMR (400MHz, CD₃OD) δ 7.44 (d, J = 7.6 Hz, 0.5H), 7.29 (s, 1H), 7.23 (d, J - 8.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.08 (d, J = 9.6 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.04 (m, 2H), 3.89 (m, 2H), 3.55 (m, 2H), 2.83 (m, 1H), 2.35 (m, 1H), 2.17 (m, 2H), 1.99 (m, 1H), 1.75 (m, 5H), 1.56 (m, 1H), 1.38 (m, 1H), 1.20 (s, 9H); LCMS (ESI): RT = 0.861 minutes, m/z 442.2 [M+H+], method=10-80AB/2 min ELSD.

[00218] N-((2 ,4a'/?,9a^,5)-2-Amino-7'-(tetrahydro-2H-pyran-4-yl)-l',2',3',4^,,4a',9a'- hexahydro-5H-spiro[oxazole-4,9^,-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.44 (d, J = 7.2 Hz, 0.8H), 7.29 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.08 (d, J = 9.6 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.04 (m, 2H), 3.89 (m, 2H), 3.55 (m, 2H), 2.83 (m, 1H), 2.35 (m, 1H), 2.17 (m, 2H), 1.99 (m, 1H), 1.75 (m, 5H), 1.56 (m, 1H), 1.38 (m, 1H), 1.20 (s, 9H); LCMS (ESI): RT = 0.862 minutes, m/z 442.2[M+H+], method- 10-80 AB/2 min ELSD. Example 32

N-((4S.4a'i^.9a'S)-2-amino-7'-isopropyl-1 2^3 4 4a 9a'-hexahvdro-5H-spiroroxa2ole-4,9'- xanthen1-2'-yl)-5-methylpicolinamide

[00219] Step A: A solution of Intermediate 1 (6.0 g, 15.2 mmol), 4,4,5,5-tetramethyl-2- (prop-l-en-2-yl)-l,3,2-dioxaborolane (3.8 g, 22.8 mmol), Pd(PPh₃)₂Cl₂ (1.1 g, 1.5 mmol) and Na₂C0₃ (4.8 g, 45.6 mmol) in dioxane/H₂0 (120/40 mL) was stirred at 100°C for 2.5 hours. Water was added, and the mixture was extracted with EtOAc (3 X 100 mL), the organic layer was dried over Na₂S0₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate in petroleum ether) to yield the product (3.3 g, 80.0% purity) that was used without fur her purification.

Intermediate 1

[00220] Step B: A mixture of the product of Step A (3.3 g, 9 mmol) and Pd/C (960 mg) in MeOH (50 ml) was stirred at room temperature under H₂ atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the product (2.5 g, 75.8%). 1H NM (CD₃OD, 400 MHz) δ 7.16 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 2.0, 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 9.2 Hz, 1H), 3.97-3.84 (m, 6H), 2.87-2.81 (m, 1H), 2.19-2.09 (m, 2H), 1.88-1.68 (m, 4H), 1.49 (t, J = 13.2 Hz, 2H), 1.22-1.20 (m, 6H).

[00221] Step C: A solution of the product of Step A (2.5 g, 7.0 mmol) in 3N HC1 (25 mL), acetone/THF (75/25 mL) was heated at 60°C for 16 hours. The mixture was basified with Na₂C03 until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 60 mL). The combined organic layers were dried, concentrated, and purified by trituration with PE to give (4S,4a^,i?,9a'5)-2-amino-7'-isopropyl- ,4',4a^,,9a'-tetrahydro-5H-spiro[oxazole-4,9^!-xanthen]- 2'(3'H)-one (2.0 g, crude) as a solid that was used without further purification.

[00222] Step D: Ammonium acetate (4.3 g, 56 mmol) was added to a solution of (4S,4a'_J/?,9a'S)-2-amino-7'-isopropyl-l^,,4^,,4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]- 2'(3'H)-one (1.1 g, 3.5 mmol) in MeOH (50 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (352 mg, 5.6 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHC0₃, and extracted with EtOAc (3 X 50 mL). The solvent was removed under reduced pressure to give (2'i?,4S,4a'i?,9a'iS)-7'-isopropyl- ,2^,,3',4',4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (1.1 g, crude) that was used without further purification. LCMS (ESI): RT = 2.606 minutes, m/z 316.2[M+H+]. method: 0-60AB / 7 mm.

[00223] Step E: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) at 0°C were added to a mixture of (2'i?,4S,4a'i?,9a'S)-7'-isopropyl- l^,,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and 5-methylpicolinic acid (108 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added to the mixture, and it was extracted with EtOAc. The organic layer was concentrated to give iV,N'-((4S,4a'i?,9a'5)-7^,-isopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-methylpicolinamide) (200 mg crude).

[00224] Step F: A mixture of N,N'-((4S,4a^,i?,9a^,5)-7^,-isopropyl-l ^,,2^,,3^,,4^,,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-methylpicolinamide) (200 mg, 0.36 mmol) and LiOH H₂0 (151 mg, 3.6 mmol) in MeOH/H₂0 (3/3 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated. The residue was purified by purified by pre-HPLC to give N-((4S,4a'i?,9a'S)-2- amino-7'-isopropyl- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-5- methylpicolinamide (18.5 mg). 1H NMR (CD₃OD, 400 MHz) δ 8.66 (s, 1 H), 8.34 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 2.0, 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.23 (d, J = 10.0 Hz, 1H), 4.63 (d, J = 10.0 Hz, 1H), 4.16 - 4.00 (m, 2H), 2.96- 2.89 (m, 1H), 2.57 (s, 3H), 2.45-2.38 (m, 1 H), 2.30-2.20 (m, 1H), 2.19-2.10 (m, 2H), 1.83 - 1.70 (m, 2H), 1.68 - 1.60 (m, 1H), 1.21 (dd, J = 2.0, 7.2 Hz, 6H); LCMS (ESI): RT = 0.993 minutes, m/z 435.0 [M+H+]. method = 10-80AB / 2 min.

Exam le 33

N-(f4S.4a'i?.9a'S)-2-amino-7'-isopropyl-l 2 3 4 4a 9a'-hexahvdro-5H-spiroroxazole-4.9'- xanthen1-2'-ylV5-(trifluoromethyl)picolinamide

[00225] (4S,4a'i?,9a'5)-7^,-Isopropyl-l',2',3^,,4^,,4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'- xanthene]-2,2'-diamine (100 mg, 0.32 mmol) was added at 0°C to a mixture of 5- (trifluoromethyl)picolinic acid (61 mg, 0.32 mmol) and DMTMM (132 mg, 0.48 mmol) in MeOH (5 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added to mixture, and it was extracted with EtOAc. The organic layer was concentrated, and the residue was purified by purified by pre-HPLC (basic) to give N-((4S,4a'/?,9a'5)-2-amino-7'- isopropyl-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-5- (trifluoromethyl)picolinamide (8.1 mg, 5.2% yield). Separation method: A%: H2O+0.05%NH4 (V/V); B%: CAN; Column: waters Xbridge CI 8 150*20mm*5um; 47-77% ACN; 12 minutes. 1H NMR (CD₃OD, 400 MHz) δ 8.95 (s, 1H), 8.31-8.25 (m, 2H), 7.15 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.0, 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.60 (d, J = 8.8 Hz, 1H), 4.07^.01 (m, 1H), 3.96 (d, J = 9.2 Hz, 1H), 3.90-3.83 (m, 1H), 2.86-2.79 (m, 1H), 2.31-2.28 (m, 1H), 2.08-1.92 (m, 3H), 1.72-1.58 (m, 2H), 1.46-1.37 (m, 1H), 1.21 (dd, J = 2.0, 7.2 Hz, 6H); LCMS (ESI): RT = 1.018 minutes, m/z 488.9[M+H+]. method = 10-80AB / 2 min ELSD.

Example 34

N-((2' ?,4^.4a'i?.9a'5^r)-2-amino-7'-isopropyl-l'.2'.3'.4',4a',9a'-hexahvdro-5H-spiroroxazole-4.9'- xanthen -2'-yl)-4-(difluoromethyl)benzamide

[00226] Step A: A mixture of methyl 4-formylbenzoate (1.4 g, 8.5 mmol) and DAST (6 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM, the organic layer was concentrated. The residue was purified by column to give methyl 4-(difluoromethyl)benzoate (1.1 g, 69.0% yield). 1H NMR (CDC1₃, 400 MHz) δ 8.13- 8.11 (m, 2H), 7.59-7.57 (m, 2H), 6.82 (t, J = 56 Hz, 1H), 3.94 (s, 3H).

[00227] Step B: A mixture of methyl 4-(difluoromethyl)benzoate (1.1 g, 5.9 mmol) and LiOH H₂0 (1.24 g, 29.5 mmol) in THF/H₂0 (30/10 mL) was stirred at room temperature for 3 hours. The mixture was acidified by IN HC1 to a pH of 2 and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give 4-(difluoromethyl)benzoic acid (1.0 g, 98.0% yield). [00228] Step C: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (4S,4a'i?,9a'S)-7'-isopropyl- l^,,2',3^,,4',4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and 4-(difluoromethyl)benzoic acid (136 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give N,N'-((4S,4a'/?,9a'5 -7'- isopropyl- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(4- (difluoromethyl)benzamide) (200 mg crude).

[00229] Step D: A mixture of N^^,-((4S,4a'i?,9a'S)-7^,-isopropyl-l',2^,,3',4^,,4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(4-(difluoromethyl)benzamide) (200 mg, 0.32 mmol) and LiOH H₂0 (134 mg, 3.2 mmol) in MeOH/H₂0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure to give the crude product, which was purified by pre- HPLC to give N-((2^,J?,4S,4a^,J?,9a'5)-2-amino-7'-isopropyl-l^,,2',3^,,4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)-4-(difluoromethyl)benzamide (23.3 mg). Separation method: A%: H2O+0.05%NH4 (V/V); B%: CAN; Column: YMC-Actus Triart CI 8 150mm*30mm*5um; 54-64 ACN; 12min. 1H NMR (CD₃OD, 400 MHz) δ 7.93 (t, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 1.5 Hz, 1H), 7.02-6.64 (m, 3H), 4.59 (d, J = 8.4 Hz, 1H), 4.11-3.96 (m, 2H), 3.88-3.81 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (d, J = 8.4 Hz, 1H), 2.09 (d, J = 10.8 Hz, 2H), 1.99-1.93 (m, 1H), 1.70-1.53 (m, 2H), 1.43-1.31 (m, lH), 1.19 (d, J = 6.0 Hz, 6H); LCMS (ESI): RT = 0.934 minutes, m/z 470.2[M+H+]. method = 10-80AB / 2 min.

Exam le 35

N-((2'i?.4S^a'i?,9a^,^-2-amino-7'-isopropyl-l',2',3'.4'.4a^,.9a^,-hexahvdro-5H-spiroroxazole-4.9'- xanthen]-2'-yl)-3-chloro-5-(trifluoromethyf)picolinamide N- 2'/^,4S.4a'j^.9a^,S -2-amino-7'-isopropyl-1 2 3^4'.4a 9a'-hexahvdro-5H-spiroroxazole-4.9'- xanthen]-2'-ylV3-methoxy-5-(trifluoromethyl)picolinamide

[00230] Step A: A mixture of 2,3-dichloro-5-(trifluoromethyl)pyridine (2.0 g, 9.3 mmol),

Pd(OAc)₂ (11 mg, 0.05 mmol), dppf (1.5 g, 2.8 mmol) and NaOAc (1.5 g, 18.5 mmol) was stirred at 80°C under CO (15 atm) for 5 hours. The mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by column to give ethyl 3-chloro-5- (trifluoromethyl)picolinate (1.8 g, 76% yield). 1H NMR ((CD₃)₂SO, 400 MHz) δ 9.01 (d, J = 0.8 Hz, 1H), 8.68 (dd, J = 0.4, 1.2 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).

[00231] Step B: A mixture of ethyl 3-chloro-5-(trifluoromethyl)picolinate (500 mg, 2.0 mmol) and LiOH H₂0 (1.24 g, 29.6 mmol) in THF/H₂0 (12/4 mL) was stirred at room temperature for 3 hours. The mixture was concentrated, then dissolved in DCM, filtered and the filtrate was concentrated to give 3-chloro-5-(trifluoromethyl)picolinic acid (400 mg, 90% yield). 1H NMR ((CD₃)₂SO, 400 MHz) δ 8.96 (s, 1H), 8.61 (s, 1H).

[00232] Step C: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (45',4a'^,9a^,5)-7'-isopropyl- l',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2^,-diamine (100 mg, 0.32 mmol) and 3-chloro-5-(trifluoromethyl)picolinic acid (136 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give N,iV- ((45,4a'i?,9a^*S)-7'-isopropyl-l',2^,,3',4^,,4a^,,9a^,-hexahydro-5H-spiro[oxazole-4,9^,-xanthene]-2,2'- diyl)bis(3-chloro-5-(trifluoromethyl)picolinamide) (200 mg crude).

[00233] Step D: to a mixture of N,iV-((4-S',4a' ^,9a^,5)-7'-isopropyl-l',2',3',4',4a',9a^,- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(3-chloro-5-

(trifluoromethyl)picolinamide) (200 mg, 0.32 mmol) and LiOH H₂0 (134 mg, 3.2 mmol) in MeOH/H₂0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure to give the crude product, which was purified by pre-HPLC to give N-((2'i?,45',4a'i?,9a'S)-2-amino-7'-isopropyl- l'^'^'^'^a'^a'-hexahydro-SH-spirofoxazole^^'-xanthenl^'-y -S-chloro-S- (trifluoromethyl)picolinamide (8.5 mg, 5.1%) and N-((2^,i?,4₁S',4a'i?,9a'S)-2-amino-7'-isopropyl- l',2',3',4',4a',9a^,-hexahydro-5H-spiro[oxazole-4,9^,-xanthen]-2'-yl)-3-methoxy-5- (trifluoromethyl)picolinamide (10.9 mg, 6.6%). Separation method: A%: H2O+0.05%NH4 (V/V); B%: CAN; Column: YMC-Actus Triart C18 150mm*30mm*5um; 49-69 ACN; 12min.

[00234] N-((2'/?,4S,4a^,i?,9a'S)-2-Amino-7^,-isopropyl-l^,,2^,,3^,,4^,,4a^*,9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)-3-chloro-5-(trifluoromethyl)picolinamide: 1H NMR (CD₃OD, 400 MHz) δ 8.87 (d, J = 0.8 Hz, 1H), 8.39 (d, J = 1.2 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.4, 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 9.2 Hz, 1H), 4.07 - 4.00 (m, 2H), 3.92 - 3.85 (m, 1H), 2.89 - 2.82 (m, 1H), 2.35 - 2.31 (m, 1H), 2.18 (d, J = 11.6 Hz, 2H), 2.04 - 1.97 (m, 1H), 1.79 - 1.68 (m, 1H), 1.63 - 1.53 (m, 1H), 1.41 - 1.27 (m, 1H), 1.19 (dd, J = 2.0, 6.9 Hz, 6H); LCMS (ESI): RT = 1.121 minutes, m/z 523.0[M+H+]. method = 10-80AB / 2 min ELSD. [00235] N-((2' ?,4S,4a'i?,9a^,5)-2-Amino-7^,-isopropyl-l',2',3',4',4a',9a^,-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)-3-methoxy-5-(trifluoromethyl)picolinamide: 1H NM (CD₃OD, 400 MHz) δ 8.48 (d, J = 0.4 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 2.0, 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.62 (d, J = 8.8 Hz, 1H), 4.06 - 3.99 (m, 5H), 3.91 - 3.84 (m, 1H), 2.89 - 2.82 (m, 1H), 2.34 - 2.29 (m, 1H), 2.16 (d, J = 12.8 Hz, 2H), 2.03 - 1.96 (m, 1H), 1.79 - 1.68 (m, 1H), 1.63 - 1.53 (m, 1H), 1.41 - 1.27 (m, 1H), 1.19 (dd, J = 2.0, 6.9 Hz, 6H); LCMS (ESI): RT = 1.100 minutes, m/z 519.0[M+H+]. method = 10-80AB / 2 min_ELSD.

Example 36

-r(2'i?.4S.4a'7?.9a'5^r)-2-amino-7'-isopropyl-l ',2',3'.4^,.4a'.9a'-hexahvdro-5H-spiroroxazole-4,9'- xanthenl-2'-yl)-5-methoxypicolinamide

N-(r2 ,4S.4a'i?.9a^,^-2-amino-7'-isopropyl-l '.2^,.3'.4'.4a'.9a'-hexahvdro-5H-spiroroxazole-4,9'- xanthen1-2'-yl)-5-methoxypicolinamide

[00236] Step A: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (45^,,4a'i?,9a'5)-7'-isopropyl- r,2',3',4',4a^!,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and 5-methoxypicolinic acid (121 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give N, V-((4S',4a'i?,9a^,5)-7'-isopropyl- l^,,2',3',4',4a',9a^,-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5- methoxypicolinamide) (200 mg crude).

[00237] Step B: A mixture of N V-((4₁S,4a'i?,9a^,S)-7^,-isopropyl-l',2',3',4',4a',9a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-methoxypicolinamide) (200 mg, 0.32 mmol) and LiOH H₂0 (134 mg, 3.2 mmol) in MeOH/H₂0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure to give the crude product, which was purified by pre-HPLC to give N-((2^,i?,45,4a' ?,9a'5)-2-amino-7'-isopropyl-l^,,2^,,3^,,4',4a',9a'-hexahydro-5H-spiro[oxazole- 4,9'-xanthen]-2'-yl)-5-methoxypicolinamide (1 1.1 mg) and N-((2'S,4S,4a'^,9a'5)-2-amino-7'- isopropyl-l',2',3',4^,,4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-5- methoxypicolinamide (5.7 mg). Separation method: A%: H2O+0.05%NH4 (V/V); B%: CAN; Column: YMC-Actus Triart C18 150mm*30mm*5um; 54-64 ACN; 12min.

[00238] N-((2'^,4S,4a'i?,9a'S)-2- Amino-7'-isopropyl- 1 '^'^'^'^a'^a'-hexahydro-SH- spiro[oxazole-4,9'-xanthen]-2'-yl)-5-methoxypicolinamide: Ή NMR (CD₃OD, 400 MHz) δ 8.30 (t, J = 2.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 2.4, 8.8 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 8.8 Hz, 1H), 4.04(d, J = 8.8 Hz, 2H), 3.95

- 3.86 (m, 4H), 2.89 - 2.82 (m, 1H), 2.32 (d, J = 8.4 Hz, 1H), 2.10 - 1.97 (m, 3H), 1.76 - 1.58 (m, 2H), 1.48 - 1.39 (m, 1H), 1.19 (d, J = 6.0 Hz, 6H); LCMS (ESI): RT = 1.090 minutes, m/z 450.9[M+H+]. method = 10-80AB / 2 min ELSD.

[00239] N-((2'S,4S,4a7?,9a'S)-2- Amino-7-isopropyl- 1 ',2',3 ^4a^9a'4_exahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)-5-methoxypicolinamide: Ή NMR (CD₃OD, 400 MHz) δ 8.27 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 2.8, 8.8 Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 9.2 Hz, 1H), 4.41(s, 1H), 4.08(d, J = 8.8 Hz, 2H), 4.01

- 3.93 (m, 4H), 2.88 - 2.81 (m, 1H), 2.22 - 2.03 (m, 4H), 1.93 - 1.81 (m, 2H), 1.65 - 1.59 (m, H), 1.19 (d, J - 6.0 Hz, 6H); LCMS (ESI): RT = 1.117 minutes, m/z 451.0[M+H+]. method = 10-80AB / 2 min ELSD.

Example 37

N-((2'^j?.4S.4a' ?.9a'S -2-amino-7'-isopropyl-l'.2'.3'.4',4a'.9a'-hexahvdro-5H-spiroroxazole-4.9'- xanthenl-2'-yl)-5-methylpyrazine-2-carboxamide

[00240] Step A: A solution of (2'i?,45,4a^,i?,9a^,S)-7'-isopropyl-l',2^,,3',4',4a',9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol), 5-methylpyrazine-2- carboxylic acid (1 10 mg, 0.79 mmol), HATU (362 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) in DCM (8 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic layer was concentrated to give N,N"- ((2^,45,4a'i?,9a'S)-7'-isopropyl-l',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]- 2,2'-diyl)bis(5-methylpyrazine-2-carboxamide) (200 mg, crude) that was used without further purification.

[00241] Step B: A mixture of N,N'-((2'i^,4S,4a^, _J?^,9a'5)-7'-isopropyl-l',2',3',4^,,4a',9a^,- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2^,-diyl)bis(5-methylpyrazine-2-carboxamide) (200 mg, 0.32 mmol) and LiOH H₂0 (134 mg, 3.2 mmol) in MeOH/H₂0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure to give the crude product, which was purified by pre- HPLC to give N-((2'i?,45,4a^, ?,9a'5 -2-amino-7'-isopropyl-l',2',3^,,4^,,4a^,,9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl)-5-methylpyrazine-2-carboxamide (13.8 mg). Ή NMR (CD₃OD, 400 MHz) δ 9.07 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 0.8 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.0, 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.96 (d, J = 8.8 Hz, 1H), 3.89 - 3.82 (m, 1H), 2.86 - 2.79 (m, 1H), 2.63 (s, 3H), 2.31 - 2.27 (m, 1H), 2.08 - 1.92 (m, 3H), 1.74 - 1.60 (m, 2H), 1.46 - 1.37 (m, 1H), 1.21 (dd, J = 2.0, 7.2 Hz, 6H); LCMS (ESI): RT = 0.953 minutes, m/z 436.1 [M+H+]. method = 10-80AB / 2 min ELSD.

Example 38

N-((2'/?.4S.4a'J?.9a'^-2-amino-7'-isopropyl-l 2 3 4'.4a'.9a'-hexahvdro-5H-spiro[oxazole-4,9'- xanthen] -2'- yl )pyrimidine-4-carboxamide

[00242] Step A: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0°C to a mixture of (4S,4a'i?,9a'5)-7'-isopropyl- l^,,2',3^,,4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and pyrimidine-4-carboxylic acid (134 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give N,N'-((4S',4a'i?,9a'5)-7'-isopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(pyrimidine-4- carboxamide) (200 mg crude) that was used without further purification.

[00243] Step B: A mixture of N,iV-((45,4a'i?,9a'5)-7^,-isopropyl-l',2^,,3',4',4a',9a'- hexahydro-5H-spiro [oxazole-4,9'-xanthene] -2,2'-diyl)bis(pyrimidine-4-carboxamide) (200 mg, 0.32 mmol) and LiOH H₂0 (134 mg, 3.2 mmol) in MeOH/H₂0 (5/5 mL) was stirred at reflux for 1.5 hours. Water was added, and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure to give the crude product, which was purified by pre-HPLC to give N-((2' ?,4S,4a'i?,9a'5)-2-amino-7'-isopropyl- 1 ',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole- 4,9'-xanthen]-2'-yl)pyrimidine-4-carboxamide (10.4 mg). Separation method: A%: H2O+0.05%NH4 (V V); B%: CAN; Column: YMC-Actus Triart CI 8 150mm*30mm*5um; 46% ACN; 12min. ^lH NMR (CD₃OD, 400 MHz) δ 9.26 (d, J = 1.6 Hz, 1H), 9.01 (d, J = 5.2 Hz, 1H), 8.07 (dd, J = 1.2, 4.8 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 2.4, 8.4 Hz, 1H), 6.70 (d, J - 8.4 Hz, 1H), 4.76 (d, J = 9.2 Hz, 1H), 4.14(d, J = 9.2 Hz, 2H), 4.07 - 4.01 (m, 1H), 3.92 - 3.86 (m, 1H), 2.87 - 2.80 (m, 1H), 2.32 (t, J = 4.0 Hz, 1H), 2.07 - 1.98 (m, 3H), 1.72 - 1.63 (m, 2H), 1.52 - 1.41 (m, 1H), 1.21 (dd, J = 2.0, 6.8 Hz, 6H); LCMS (ESI): RT = 0.832 minutes, m/z 422.1 [M+H+]. method = 10-80AB / 2 min ELSD.

Example 39

N-((2'S.4i?.4a'S.9a'/?)-2-amino-7^,-(trifluoromethoxyVl'.2^,.3^,.4^,.4a'.9a'-hexahvdro-5H- spiro[oxazole-4,9'-xanthenl-2'-yl)pivalamide

N-((2'i?,4i?,4a .9a'i?)-2-amino-7'-(trifluoromethoxy)-l'.2',3'.4'.4a'.9a'-hexahvdro-5H- spiro[oxazole-4,9'-xanthen1-2'-vPpivalamide

[00244] Step A: BBr₃ (85.2 g, 341 mmol) was added dropwise at -20°C under N₂ to a solution of 2-methoxy-5-(trifluoromethoxy)benzaldehyde (50.0 g, 227 mmol) in DCM (500 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was worked up by adding ice chips, then the mixture was poured into saturated aqueous NaHC0₃ (300 mL), and extracted with DCM (3 X 400 mL). The combined organic layers were dried and concentrated to afford the crude product, which was purified by silica gel (hexanes: EtOAc = 20:1) to give 2- hydroxy-5-(trifluoromethoxy)benzaldehyde (38.0 g, 81.0% yield). Ή NMR (400MHz, CDC1₃) δ 10.97 (s, 1H), 9.87 (s, 1H), 7.43-7.38 (m, 2H), 7.02 (d, J = 8.0 Hz, 1 H).

[00245] Step B: A solution 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (36.6 g, 178 mmol), 4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)morpholine (40.0 g, 178 mmol) in toluene (70 mL) was stirred at room temperature for 24 hours. The mixture was filtered and washed with a minimal amount of toluene. The solid was dried in a vacuum oven at 50°C overnight to give 4a'- mo holino-7'-(trifluoromethoxy)-Γ,3',4',4a',9',9a'-hexahydrospiro[[l,3]dioxolane-2,2'-xanthen]- 9'-ol (38.0 g, crude) that was used without further purification.

[00246] Step C: A solution of 4a^,-mo holino-7'-(trifluoromethoxy)-l^,,3',4^,,4a',9^,,9a^,- hexahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'-ol (67.2 g, 156 mmol) in DCM (400 mL) was cooled to 0°C and Dess-Martin reagent (79.0 g, 187 mmol) was added in portions. The mixture was stirred at room temperature for overnight. The reaction mixture was diluted with DCM (400 mL), then slowly quenched with 2N NaOH. The mixture was poured into a separatory funnel, rinsing the flask with DCM and water. The organic layer was washed successively with 2N NaOH (2 X 900 mL), 2N HC1 (2 X 900 mL), water (900 mL), brine (900 mL), dried and concentrated to afford a solid, which was triturated with ether to give 7'-(trifluoromethoxy)-3',4'- dihydrospiro[[l ,3]dioxolane-2,2'-xanthen]-9'(l 'H)-one (52.5 g) as a solid.

[00247] Step D: A solution of compound 5 (52.5 g, 154 mmol) in THF (800 ml) was cooled to -70°C, and L-Selectride® (1.0 M in THF , 230 mL, 230 mmol) was added dropwise.

The reaction was stirred at -70°C for 2 hours and then quenched at -70°C with saturated NFL;C1 (10 mL). The suspension was stirred vigorously while warming to room temperature. The reaction mixture was diluted with ethyl acetate (800 mL) and water (800 mL) with constant stirring. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with ethyl acetate (3 X 800 mL). The combined organic layers were dried and concentrated to afford the crude product, which was purified by silica gel (PE: EtOAc, 20: 1 to 5: 1) to give the product (4a ,9a'5)-7^,-(trifluoromethoxy)-l ',4',4a',9a'-tetrahydrospiro[[l ,3]dioxolane-2,2'- xanthen]-9'(3'H)-one (17.0 g, trans) as a solid.

[00248] Step E: Tebbe reagent (0.60M in toluene, 200 mL, 120 mmol) was slowly added at 0°C to a solution of (4a'S,9a'S)-7'-(trifluoromethoxy)-l ',4',4a^,,9a'- tetrahydrospiro[[l,3]dioxolane-2,2'-xanthen]-9'(3'H)-one (17.0g ,48mmol) in THF (250 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by 2N NaOH. Na₂S0₄ was added to this stirring mixture, and the reaction mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel (PE:EtOAc, 1 :40) to give 9'- methylene-7'-(trifluoromethoxy)- ,3',4',4a',9',9a^,-hexahydrospiro[[l ,3]dioxolane-2,2'-xanthene] (15.0 g, 89.9% yield) as a solid. 1H NMR (400 MHz, CDC1₃) δ 7.35 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 2.0, 8.0 Hz, 1H), 6.82 ((d, J = 8.0 Hz, 1H), 5.49 (d, J = 2.4 Hz, 1H), 4.92 (d, J = 2.4Hz,lH), 4.03-3.98 (m, 4H), 3.74-3.67 (m, 1H), 2.61-2.55 (m, 1H), 2.26-2.13 (m, 2H) , 2.00- 1.85 (m, 2H), 1.70-1.50 (m, 2H).

[00249] Step F: A solution of iodine (13.4 g, 52.5 mmol) in EtOAc (150 mL) was added dropwise to a suspension of AgOCN (9.15 g, 61.4 mmol) and 9'-methylene-7'- (trifluoromethoxy)-l',3',4',4a',9',9a'-hexahydrospiro[[l ,3]dioxolane-2,2'-xanthene] (15 g, 43.8 mmol) in acetonitrile (150 mL ) and EtOAc(150 mL) at 0°C. After 3 hours, the reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure. The residue was dissolved in THF (750 mL), and NH₄OH (230 mL, 25% w/w) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated NaHC0₃ (300 mL), and the aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organic layers were dried and concentrated to afford the crude product, which was purified by trituration with PE to give the product as a solid (15.6 g, mixture of two diastereomers, 74.3% of yield).

[00250] Step G: A solution of the product of Step F (15.6 g, 39 mmol) in 3N HC1 (150 mL) and acetone (300 mL) was heated at 60°C for 16 hours. The mixture was basified with NaOH until a pH greater than 10, and the mixture was extracted with EtOAc (3 X 500 mL). The combined organic layers were dried, concentrated, and was purified by column on silica gel (Eluant: DCM:MeOH, 100: 1 to 20: 1) to give (4^,4a ,9a'i?)-2-amino-7^,-(trifluoromethoxy)- l'^'^a'^a'-tetrahydro-SH-spirotoxazole^^'-xanthenJ^ S'HI-one (3.2 g, 23% yield) and (4S,4a^,5,9a' ^)-2-amino-7'-(trifluoromethoxy)-l',4^,,4a',9a'-tetrahydro-5H-spiro[oxazole-4,9^,- xanthen]-2'(3'H)-one (3.2 g, 23% yield).

[00251] (4i?,4a ,9a^, _J/?)-2-Amino-7'-(trifluoromethoxy)-l ',4',4a',9a^,-tetrahydro-5H- spiro[oxazole-4,9'-xanthen]-2'(3'H)-one: 1H NMR (400MHz, (CD₃)₂SO) δ 7.16-7.12 (m, 2H), 6.87 (dd, J = 8.8Hz, 1H), 6.32 (s, br, 1H), 4.675 (d, J = 9.2 Hz, 1H), 4.43-4.36 (m, 1H), 3.78 (d, J = 9.2 Hz, 1H), 2.69-2.60 (m, 1H), 2.42-2.32 (m, 2H), 2.28-2.20 (m, 1H), 2.18-2.05 (m, 2H), 1.92-1.83 (m, 1H).

[00252] (4S,4a ,9a^,i?)-2-Amino-7'-(trifluoromethoxy)- 1

spiro[oxazole-4,9'-xanthen]-2'(3^*H)-one: 1H NMR (400MHz, (CD₃)₂SO) δ 7.08 (dd, J = 0.8, 8.4 Hz, 1H), 7.00 (d, J = 0.8Hz, 1H), 6.80 (dd, J = 8.8Hz, 1H), 4.28 (d, J = 9.6 Hz, 1H), 4.26-4.18 (m, 1H), 4.08 (d, J = 9.6 Hz, 1H), 2.50-2.43 (m, 1H), 2.30-2.21 (m, 2H), 2.20-2.06 (m, 3H), 1.80-1.68 (m, 1H).

[00253] Step H: Ammonium acetate (1.7 g, 22.5 mmol) was added to a solution of (4^,4a ,9a'i?)-2-amino-7'-(trifluoromethoxy)-l',4^,,4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'- xanthen]-2'(3'H)-one (500 mg, 1.4 mmol) in MeOH (20 mL). The reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, NaBH₃CN (145 mg, 2.3 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHC0₃, and extracted with DCM (3 X 50 mL). The solvent was removed under reduced pressure to give (4 ?,4a^,S^,,9a'^)-7'-(trifluoromethoxy)- ,2^,,3',4',4a',9a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (350 mg, mixture of two isomers) that was used without further purification.

[00254] Step I: 2,2-Dimethyl-propionyl chloride (150 mg, 1.3 mmol) was added dropwise at 0°C to a solution of (4i?,4a ,9a'i?)-7^,-(trifluoromethoxy)-l^,,2^,,3',4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (150 mg, 0.4 mmol) and Et₃N (240 mg, 2.5 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the mixture, and extracted with DCM (3 X 10 mL). The organic layers was concentrated to provide N,N-((4J?,4a^,S,9a'i?)-7^,-(trifluoromethoxy)-l '^'^'^'^a'^a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(2,2-dimethylpropanamide) (200 mg, mixture of two isomers) that was used without further purification.

[00255] Step J: LiOH H₂0 (265 mg, 6.3 mmol) to a solution of TV-^^a'S^a'/?)-?'- (trifluoromethoxy)- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'- diyl)bis(2,2-dimethylpropanamide) (200 mg, 0.42 mmol) in MeOH (3 mL) and water (3 mL). The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated. The residue was purified by purified by pre-HPLC to give N-((2'S,4R,4a'S,9a'R)-2-ammo-7'- (trifluoromethoxy)- ,2',3',4',4a^,,9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (19.6 mg) and N-((2^,J?,4/?,4a'S,9a^,J?)-2-amino-7^,-(trifluoromethoxy)-l',2',3^,,4',4a',9a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (6.5 mg) as a solid.

[00256] N-((2 ,4i?,4a ,9a^)-2-Amino-7'-(trifluoromethoxy)-l',2',3',4',4a',9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.18 (d, J = 2.4 Hz, 1 H), 7.08 (dd, J = 2.4, 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 3.97 (d, J = 9.2 Hz, 1H), 3.92-3.80 (m, 2H), 2.30-2.21 (m, 1H), 1.99-1.88 (m, 3H), 1.70-1.62 (m, 1H), 1.52-1.41 (m, 1H), 1.30-1.20 (m, 1H), 1.20 (s, 9H); LCMS (ESI): RT = 1.140 minutes, m/z 441.9[M+H+], method=0-60AB/2 min ELSD.

[00257] N-((2'i?,4i?,4a'S,9a'7?)-2-Amino-7'-(trifluoromethoxy)- 1 '^'^'^'^a'^a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400 MHz, CD₃OD) δ 7.18 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 2.4, 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 8.8 Hz, 1H), 4.18-4.10 (m, 1H), 4.00-3.93 (m, 1H), 3.93 (d, J = 8.8 Hz, 1H), 2.12-1.93 (m, 4H), 1.80-1.70 (m, 2H), 1.53-1.47 (m, 1H), 1.20 (s, 9H); LCMS (ESI): RT = 1.177 minutes, m/z 442.0[M+H+], method=0-60AB/2 min ELSD.

Exam le 40

N-((2 .4i?.4a .9a'J?V2-amino-7'-(trifluoromethoxy -l '.2',3'.4'.4a'.9a^,-hexahvdro-5H- spiro oxazole-4,9'-xanthen1-2'-yl)-5-chloropicolinamide

N-((2'S.4S.4a'S,9a'i?)-2-amino-7^,-(trifluoromethoxy - Γ.2',3 '.4'.4a'.9a'-hexahvdro-5H- spiro [oxazole-4.9'-xanthen] -2'-yl)-5 -chloropicolinamide [00258] Step A: EDCI (270 mg, 1.4 mmol), HOBT (190 mg, 1.4 mmol) and DIPEA (353 mg, 2.8 mmol) was added at 0°C to a mixture of (4i?,4a'S,9a'i?)-7'-(trifluoromethoxy)- l',2',3',4^,,4a',9a'-hexahydro-5H-spiro[oxazole-4,9^,-xanthene]-2,2'-diamine (200 mg, 0.56 mmol) and 5-chloropicolinic acid (205 mg, 1.3 mmol) in DCM (20 mL). The mixture was stirred at room temperature overnight. Saturated NaHC0₃ was added, and the mixture was extracted with EtOAc, the organic layer was concentrated to give N,N^,-((4i?,4a'S,9a^,i?)-7^,-(trifIuoromethoxy)- 1^2^3^4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-chloropicolinamide) (280 mg crude).

[00259] Step B: A mixture of N^'-((4J?,4a ,9a'i?)-7^,-(trifluoromethoxy)-l '^'^'^'^a'^a'- hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(5-chloropicolinamide) (280 mg, 0.44 mmol) and LiOH H20 (296 mg, 7.0 mmol) in MeOH/H20 (8/8 mL) was stirred at reflux for 1.5 h. Water was added and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure to give the crude product which was purified by pre-HPLC to give N- ((2 ,4Λ,4a ,9a'i^)-2-amino-7'-(trifluoromethoxy)-1^2 3^,,4^,,4a',9a'-hexahydro-5H-spiro[oxazole- 4,9'-xanthen]-2'-yl)-5-chloropicolinamide (21.7 mg, 15.6% yield) and N-((2 ,45,4a'S,9a' ?)-2- amino-7'-(trifluoromethoxy)-r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)- 5-chloropicolinamide (15.1 mg, 1 1.0% yield). Separation method: Pre-HPLC (HCOOH): Instrument=Gilson-281, Column=YMC-Actus/75*30mm, Mobile phase = MeCN:16%-46%; H2O(+0.001HCOOH+0.00025HCl), Rate=25 niL/min, Monitored Wavelength=220nm/254 nm, Run length=10 min/ 15 min, Column temperature=40°C.

[00260] N-((2'5,4i?,4a ,9a'i?)-2-amino-7'-(trifluoromethoxy)- 1 '^'^'^'^a'^a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-5-chloropicolinamide: 1H NMR (CD₃OD, 400 MHz) δ 8.65 (t, J = 1.6Hz, 1H), 8.10 (d, J = 8.4Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.53 (s, 1H), 7.26-7.24 (m, 1H), 6.96 (d, J = 9.2Hz, 1H), 5.20 (d, J = 10.0Hz, 1H), 4.61 (d, J = 10.0Hz, 1H), 4.10-4.05 (m, 2H), 2.40-2.35 (m, 1H), 2.26-2.21 (m, 1H), 2.12-2.04 (m, 2H), 1.81-1.70 (m, 2H), 1.62-1.53 (m, 1H); LCMS (ESI): RT = 1.082 minutes, m/z496.9[M+H+], method=10-80AB/2 min.lcm.

[00261] N-((2'S,4S,4a'S,9a^)-2-amino-7'-(trifluoromethoxy)- 1 '^'^'^'^a'^a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-5-chloropicolinamide: 1H NMR (CD₃OD, 400 MHz) δ 8.62 (d, J = 2.0Hz, 1H), 8.08-8.01 (m, 2H), 7.48 (d, J = 2.8Hz, 1H), 7.23 (dd, J = 2.0, 9.2 Hz, 1H), 6.95 (d, J = 8.8Hz, 1H), 5.22 (d, J = 10.0Hz, 1H), 4.59 (d, J = 10Hz, 1H), 4.41 (s, 1H), 4.18-4.10 (m, 1H), 2.30-2.21 (m, 3H), 2.12-2.08 (m, 1H), 2.03-1.91 (m, 2H), 1.78-1.71 (m, 1H); LCMS (ESI): RT = 1.124 minutes, m/z 496.8 [M+H+], method=10-80AB/2 min.lcm. Exam le 41

^-((2'^.4^4 '^.9 './?)-2- ηιίηο-7'-αΗίΊηοΓοηΐ6Φοχν)-1',2',3'.4'.4α'.93'-1ΐ6Χ3ΐιν(ΐΓθ-5^

spiro[oxazole-4,9'-xanthen1-2'-yl)pivalamide

N-((2'/?.4^4a .9a'i?V2-amino-7'-(trifluoroniethoxyV 1 '.2'.3 '.4'.4a'.9a'-hexahvdro-5H- spiro[oxazole-4,,9'-xanthen^"|-2'-vDpivalamide

[00262] Step A: A suspension of (4S,4a'S,9a' ?)-2-amino-7^,-(trifluoromethoxy)- l 4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]-2'(3'H)-one (1.0 g, 2.8 mmol), NH₂OH HCl (1.0 g, 14.0 mmol) and NaOAc (1.2 g, 14.0 mmol) in MeOH (40 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with EtOAc (3 X 50 mL). The organic layers was concentrated to provide (9aS,14S,14ai?)-5H-2- amino-7'-(trifluoromethoxy)-1^4 4a^9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]-2 3'H)-one oxime (1.0 g, crude) that was used without further purification.

[00263] Step B: Raney Ni (1.0 g) was added to a solution of compound (9aS,14S,14a7?)- 5H-2-amino-7'-(trifluoromethoxy)-r,4',4a',9a'-tetrahydro-5H-spiro[oxazole-4,9'-xanthen]- 2'(3'H)-one oxime (1.0 g, 2.7 mmol) in MeOH (40 mL) and NH₃ H₂0 (20 mL). The reaction mixture was stirred under ¾ (1 atm) at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to provide (4S,4a ,9a'i?)-7'-(trifluoromethoxy)- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (900 mg, mixture of two isomers) that was used without further purification.

[00264] Step C: 2,2-Dimethyl-propionyl chloride (200 mg, 1.7 mmol) was added dropwise at 0°C to a solution of (4S,4a'S,9a' ?)-7'-(trifluoromethoxy)-l^,,2',3^,,4',4a^,,9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (200 mg, 0.56 mmol) and Et₃N (340 mg, 3.4 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the mixture, and extracted with DCM (3 X 20 mL). The organic layers was concentrated to provide N^V'-((4S,4a^,S,9a'i?)-7'-(trifluoromethoxy)-l',2',3',4',4a',9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(2,2-dimethylpropanamide) (280 mg, mixture of two isomers) that was used without further purification.

[00265] Step D: to a solution of N^V-((4S,4a'S,9a'i?)-7'-(trifluoromethoxy)- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(2,2- dimethylpropanamide) (280 mg, 0.53 mmol) in MeOH (6 mL) and water (6 mL) was added LiOH H₂0 (336 mg, 8.0 mmol). The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, water was added, and the mixture was extracted with EtOAc. The organic layer was concentrated. The residue was purified by purified by pre-HPLC to give N- ((2 ,4S,4a ,9a'^)-2-amino-7'-(trifluoromethoxy)-1^2',3',4^*,4a',9a^,-hexahydro-5H-spiro[oxazole- 4,9'-xanthen]-2'-yl)pivalamide (60.1 mg) and N-((2'J?,4S,4a'₁?,9a'i?)-2-amino-7'- (trifluoromethoxy)- ,2^,,3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide (13.2 mg) as a solid.

[00266] N-((2^,S,4S,4a'5,9a'i?)-2-Amino-7'-(trifIuoromethoxy)-l',2',3',4^,,4a^,,9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.11 (s, 1H), 7.08 (d, J = 8.8Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.49-4.40 (m, 2H), 3.98-3.80 (m, 2H), 2.30- 2.22 (m, 1H), 1.91-1.80 (m, 3H), 1.71-1.62 (m, 1H), 1.49-1.30 (m, 2H), 1.15 (s, 9H); LCMS (ESI): RT = 1.063 minutes, m/z 441.9[M+H+], method=10-80AB/2 min ELSD.

[00267] N-((2^,45,4a'S,9a'^)-2- Amino-7'-(trifluoromethoxy)- 1 ^*,2',3 '^'^a'^a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)pivalamide: 1H NMR (400MHz, CD₃OD) δ 7.12 (s, 1H), 7.08 (d, J = 9.2Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.32 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 4.10-3.97 (m, 1H), 2.10-1.89 (m, 4H), 1.82-1.49 (m, 3H), 1.20 (s, 9H); LCMS (ESI): RT = 1.119 minutes, m/z 441.9[M+H+], method=10-80AB/2 min ELSD.

Example 42

N-((2'SASAa!S.9a!R V2-amino-7'-(trifluoromethoxyV 1 '.2'.3 '.4'.4a'.9a'-hexahydro-5H- spiro oxazole-4,9'-xanthen1-2'-yl)-l-(trifluoromethyl)cvclopropanecarboxamide

N-(r2^,i?,4₁S.4a'S.9a'i?V2-amino-7'-(trifluoromethoxy -l',2^,.3'.4^,.4a^,.9a'-hexahvdro-5H- spiro[oxazole-4,9'-xanthen]-2'-yl -l-(trifluoromethyl)cyclopropanecarboxamide

[00268] Step A: EDCI (201 mg, 1.05 mmol) and HOBt (135 mg, 1.05 mmol) were added at 0°C to a solution of (4₁S,4a ,9a'^)-7'-(trifluoromethoxy)-l',2',3^,,4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (150 mg, 0.42 mmol), 1- (trifluoromethyl)cyclopropanecarboxylic acid (165 mg, 1.05 mmol) and Et₃N (105 mg, 1.05 mmol) in DCM (6 mL). The mixture was stirred at room temperature for overnight. Water (10 mL) was added to the mixture, and extracted with DCM (3 X 10 mL). The organic layers were concentrated to provide N^V-((45',4a'5',9a'i?)-7'-(trifluoromethoxy)-l^,,2',3',4',4a',9a'-hexahydro- 5H-spiro [oxazole-4,9'-xanthene] -2,2'-diyl)bis( 1 -(trifluoromethyl)cyclopropanecarboxamide) (165 mg, 90% of yield) that was used without further purification.

[00269] Step B: LiOH (270 mg, 6.3 mmol) was added to a solution of N,7V- ((4S,4a ,9a^,^)-7^,-(trifluoromethoxy)- 1 ',2',3 ^4^4^9a^,-hexahydro-5H-spnO[oxazole-4,9'- xanthene]-2,2'-diyl)bis(l-(trifluoromethyl)cyclopropanecarboxamide) (165 mg, 0.42 mmol) in MeOH (3 mL) and water (3 mL). The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was extracted with DCM (3 X 50 mL). The solvent was removed under reduced pressure to give the crude product, and the crude product was purified by pre-HPLC (base) to give N-((2'S,4S,4a'S,9a'i?)-2-amino-7'-(trifluoromethoxy)- l'^'^'^'^a'^a'-hexahydro-SH-spirotoxazole^^'-xanthe^^'-y -l-

(trifluoromethyl)cyclopropanecarboxamide (10.7 mg) and N-((2'^,4S,4a'S,9a'i?)-2-amino-7'- (trifluoromethoxy)- ,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9^,-xanthen]-2'-yl)-l- (trifluoromethyl)cyclopropanecarboxamide (10.0 mg mixture, including 33% of N- ((2 ,4S,4a ,9a'i?)-2-amino-7^,-(trifluoromethoxy)-1^2^,,3',4',4a',9a^,-hexahydro-5H-spiro[oxazole- 4,9^,-xanthen]-2'-yl)-l-(trifluoromethyl)cyclopropanecarboxamide) as a solid.

[00270] N-((2^,S,4S,4a'S,9a^,^)-2-Amino-7^,-(trifluoromethoxy)-l',2',3',4',4a',9a^,-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)- 1 -(trifluoromethyl)cyclopropanecarboxamide: 1H NMR (400MHz, CD₃OD) δ 7.11 (d, J = 2.4 Hz, IH), 7.07 (dd, J = 2.4, 8.8 Hz, IH), 6.85 (d, J = 8.8 Hz, IH), 4.50-4.40 (m, 2H), 3.98-3.80 (m, 2H), 2.30-2.20 (m, IH), 1.98-1.80 (m, 3H), 1.72-1.60 (m, IH), 1.50-1.30 (m, 2H), 1.28-1.20 (m, 4H); LCMS (ESI): RT = 1.069 minutes, m/z 493.9[M+H+], method=10-80AB/2 min ELSD.

[00271] N-((2'J?,45,4a ,9a^,^)-2-Amino-7'-(trifluoromethoxy)-l^,,2^,,3^,,4',4a',9a'-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-yl)-l-(trifluoromethyl)cyclopropanecarboxamide: ^!H NMR (400MHz, CD₃OD) δ 7.14 (d, J = 2.4 Hz, IH), 7.09 (d, J = 6.0 Hz, IH), 6.87-6.83 (m, IH), 4.58- 4.53 (m, IH), 4.38-4.33 (m, IH), 4.16-4.12 (m, IH), 3.96-3.93 (m, 2H), 2.26-2.22 (m, IH), 1.97- 1.93 (m, 3H), 1.64-1.58 (m, 3H), 1.26-1.23 (m, 4H); LCMS (ESI): RT = 1.1 10 minutes, m/z 493.9 [M+H+], method=10-80AB/2 min ELSD.

[00272] The following compounds in Table 1 were prepared according to the above procedures using appropriate intermediates. Table 1

trifluoroacetic acid

tr uoroacetc ac

trifluoroacetic acid

0 trifluoroacetic acid

trifluoroacetic acid

[00273] It will be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Thus, the foregoing description is considered as illustrative only of the principles of the invention.

[00274] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

I claimed is:

1. A compound of Formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

W is a bond or CH₂;

Y is O, S or NR^a;

Z is a CH₂ or C=0;

Xi is selected from O, S, S(O), S0₂, NR^b and CHR^b;

X₂ is selected from CR⁶ and N;

R¹ and R² are independently selected from hydrogen and C C₆ alkyl;

R³ is selected from hydrogen and C!-C₃ alkyl;

R⁴ is selected from hydrogen, halogen, CN, Ci-C alkyl, C_\-C(, alkoxy, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen;

R⁵ is selected from C C₆ alkyl, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, C_\-C alkyl optionally substituted with halogen, C₃-C cyclopropyl and C C₆ alkoxy optionally substituted with one or more R^c groups;

R⁶ is selected from hydrogen, halogen, CrC₆ alkyl and C C₆ alkoxy;

R^a is C C₃ alkyl;

R^b is selected from hydrogen, halogen and Q-C6 alkyl; and

R^c is selected from oxo and phenyl. The compound of Claim 1, having the Formula II:

II

The compound of Claim 1, having the Formula III:

III

The compound f any one of Claims 1 to 3, having the Formula IV:

5. The compound of any one of Claims 1 to 3, having the Formula V:

ompound of Claim 1 or 2, having the Formula VI:

7. The compound of Claim 1 or 2 having the Formula VII:

8. The compound of Claim 1 or 3 having the Formula VIII:

VIII

9. The compound of Claim 1 or 3 having the Formula IX:

10. The compound of any one of Claims 1 to 9, wherein:

W is a bond;

Y is O or S;

Z is CH₂;

Xi is O;

X₂ is CR⁶;

1 2

R and R are hydrogen;

R³ is selected from hydrogen and C]-C₃ alkyl;

R⁴ is selected from hydrogen, halogen, CN, C C₆ alkyl, Q-C6 alkoxy, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted with halogen; R⁵ is selected from Cj-C₆ alkyl, C₃-C₆ cycloalkyl, a 3 to 6 membered heterocyclyl, phenyl, a 5 to 6 membered heteroaryl, a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryls are optionally substituted with one or more groups selected from halogen, hydroxyl, Ci-C alkyl optionally substituted with halogen, C₃-C₆ cyclopropyl and Cj-Q alkoxy optionally substituted with one or more R^c groups;

R⁶ is selected from hydrogen and Ci-C₆ alkoxy; and

R^c is selected from oxo and phenyl.

1 1. The compound of any one of Claims 1 to 9, wherein: (a) Y is S, Z is CH₂ and W is a bond; (b) Y is O, Z is CH₂ and W is a bond; (c) Y is NR^a, Z is C=0 and W is a bond; (d) Y is NR^a, Z is C=0 and W is CH₂; or (e) Y is S, Z is CH₂ and W is CH₂.

12. The compound of any one of Claims 1 to 1 1, wherein Y is O or S, Z is CH₂ and W is a bond.

13. The compound of any one of Claims 1 to 12, wherein Y is O, Z is CH₂ and W is a bond.

14. The compound of any one of Claims 1 to 12, wherein Y is S, Z is CH₂ and W is a bond.

15. The compound of any one of Claims 1 to 14, wherein Xi is O.

16. The compound of any one of Claims 1 to 15, wherein R¹ and R² are independently selected from hydrogen and methyl

1177.. TThhee ccoompound of any one of Claims 1 to 16, wherein R³ is selected from hydrogen and methyl.

18. The compound of any one of Claims 1 to 17, wherein X₂ is CR⁶.

19. The compound of any one of Claims 1 to 18, wherein R⁶ is selected from hydrogen and methoxy.

20. The compound of any one of Claims 1 to 19, wherein R⁴ is selected from hydrogen, Br, CN, ethyl, isopropyl, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, 3-chloro-5-fluorophenyl, pyrimidin-5-yl, 5- fluoropyridin-3-yl and 5-chloropyridin-3-yl.

21. The compound of any one of Claims 1 to 20, wherein R⁵ is selected from methyl, tert-butyl, neopentyl, 2-fluoropropan-2-yl, 1,1 -difluoroethyl, 2-hydroxypropan-2- yl, l ,l ,l-trifluoro-2-methylpropan-2-yl, l-hydroxy-2-methylpropan-2-yl, difluoromethyl, cyclopropylmethyl, 2-methoxyethyl, methoxymethyl, (benzyloxy)methyl, methylacetate, 1 -methylcyclopropyl, 1 -(trifluoromethyl)cyclopropyl, 3 -methyloxetan-3 -yl, tetrahydropyran-4-yl, 2-methylpyrrolidin-2-yl, phenyl, 4-(difluoromethyl)phenyl, 2- methoxyphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 4-chloro-3-methoxyphenyl, 2- methyloxazol-4-yl, 2-methyloxazol-4-yl, 5-methyloxazol-4-yl, 4-methyloxazol-5-yl, 5- methylisoxazol-4-yl, 3-methylisoxazol-4-yl, 5-methylisoxazol-3-yl, l-methylimidazol-5- yl, l-methylimidazol-4-yl, pyridin-2-yl, pyridin-3-yl, 5chloro-3-fluoropyridin-2-yl, 5- chloropyridin-2-yl, 5-chloropyridin-3-yl, 5-fluoropyridin-2-yl, 5-methylpyridin-2-yl, 3- chloro-5-(trifluoromethyl)pyridin-2-yl, 3-methoxy-5-(trifluoromethyl)pyridin-2-yl, 5- methoxypyridin-2-yl, 3,5-difluoropyridin-2-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-2-yl, 6-methoxypyridin-3-yl, 2-methylpyridin-4- yl, 5-methylpyrazine-2-yl, pyrimidin-4-yl, 2-methylthiazol-4-yl and 5-fluoroindol-2-yl.

22. A compound of Claim 1 and named in any one of Examples 1 to 122 herein, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof.

23. A method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of any one of Claims 1 to 22.

24. A method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of any one of Claims 1 to 22.

25. The method of Claim 24, wherein the disease is Alzheimer's disease.

26. A pharmaceutical compositions comprising a compound of any one of Claims 1 to 22 and a pharmaceutically acceptable carrier, diluent or excipient.

27. Use of a compound of any one of Claims 1 to 22 in the manufacture of a medicament for the treatment of a neurodegenerative disease.

28. The use of Claim 27, wherein the disease is Alzheimer's disease.

29. A compound of any one of Claims 1 to 22 for the treatment of a neurodegenerative disease.

30. The compound of Claim 29, wherein the disease is Alzheimer's disease.