1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin D synthase inhibitors

This application is a 371 of International Application No. PCT/IB2017/056320, filed 12 Oct. 2017, which claims priority to U.S. 62/407,634 filed 13 Oct. 2016.

The present invention relates to novel compounds, to the use of the compounds as Hematopoietic Prostaglandin D Synthase (H-PGDS) inhibitors, to pharmaceutical compositions comprising the compounds and to the use of the compounds in therapy, especially in the treatment of conditions for which a H-PGDS inhibitor is indicated, such as neurodegenerative diseases and musculoskeletal diseases including Duchenne Muscular Dystrophy, where PGD 2 is considered to play a pathological role, for the use of a compound in the manufacture of a medicament for the treatment of conditions in which an inhibitor of H-PGDS is indicated, and a method for the treatment or prophylaxis of disorders in which inhibition of H-PGDS is indicated, in a human.

Prostaglandin D 2 (PGD 2 ) is a product of arachidonic acid metabolism, and is the major prostanoid mediator synthesised by mast cells in response to stimulation via multiple mechanisms and cellular activation pathways, including allergen-mediated cross-linking of high affinity IgE receptors (Lewis et al. (1982) Prostaglandin D 2 generation after activation of rat and human mast cells with anti-IgE. J. Immunol., 129, 1627-1631). Other cells such as dendritic cells, T h 2 cells, and epithelial cells also produce PGD 2 , but at lower levels than mast cells. PGD 2 mediates its effects via activation of the specific G-protein coupled receptors DP 1 (Boie et al. (1995) Molecular cloning and characterization of the human prostanoid DP receptor. ( J. Biol. Chem., 270, 18910-18916)) and DP 2 (CRTH2) (Abe et al. (1999), Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemo-attractant receptor family. ( Gene, 227, 71-77)) and also acts via the receptor for thromboxane A 2 (TXA 2 ), the TP receptor, on target cells.

Prostaglandin D synthase (PGDS) is the enzyme responsible for the catalytic isomerase conversion of prostaglandin endoperoxide PGH 2 to PGD 2 . PGD 2 is generated by the action of either H-PGDS (hematopoietic-type or H-type) or L-PGDS or (lipocalin-type or L-type) enzymes (Urade et al., (2000) Prostaglandin D synthase structure and function. Vitamins and hormones, 58, 89-120). H-PGDS activity is dependent on glutathione and plays an important role in the generation of PGD 2 by immune and inflammatory cells, including mast cells, antigen-presenting cells (e.g. dendritic cells), macrophages, and T h 2 cells, which are all key cells in the pathology of allergic disease. In contrast, L-type is glutathione-independent and is primarily located in the central nervous system, genital organs, and heart. These two isoforms of PGDS appear to have distinct catalytic properties, tertiary structure, and cellular and tissue distribution.

Using the inhibitor HQL-79, H-PGDS has also been implicated to play a role not only in allergic disease, but also other diseases such as Duchenne Muscular Dystrophy (Nakagawa et al. (2013) A prostaglandin D 2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old, Clinica Chimica Acta 423, 10-14) and (Mohri et al. (2009), Inhibition of prostaglandin D synthase suppresses muscular necrosis, Am. J. Pathol. 174, 1735-1744) and (Okinaga et al. (2002), Induction of hematopoietic prostaglandin D synthase in hyalinated necrotic muscle fibers: its implication in grouped necrosis, Acta Neuropathologica 104, 377-84), spinal cord contusion injury (Redensek et al. (2011) Expression and detrimental role of hematopoietic prostaglandin D synthase in spinal cord contusion injury, Glia 59, 603-614), neuroinflammation (Mohri et al. (2006) Prostaglandin D 2 -mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher. J. Neurosci. 26, 4383-4393), and neurodegenerative disease (Ikuko et al. (2007) Hematopoietic prostaglandin D synthase and DP 1 receptor are selectively upregulated in microglia and astrocytes within senile plaques from human patients and in a mouse model of Alzheimer disease. J. Neuropath. Exp. Neur. 66, 469-480). H-PGDS has also been implicated to play a role in metabolic diseases such as diabetes and obesity, since PGD 2 is converted to 15-deoxy-Δ 12,14 PGJ 2 , a potent ligand for PPARγ which is able to drive adipogenesis (Tanaka et al (2011) Mast cells function as an alternative modulator of adipogenesis through 15-deoxy-delta-12, 14-prostaglandin J 2 . Am. J. Physiol. Cell Physiol. 301, C1360-C1367). PGD 2 has been implicated to play a role in niacin-induced skin flushing (Papaliodis et al (2008) Niacin-induced “flush” involves release of prostaglandin D 2 from mast cells and serotonin from platelets: Evidence from human cells in vitro and an animal model. JPET 327:665-672).

Weber et al. (2010), Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D 2 synthase. Eur. J. Med. Chem. 45, 447-454, Carron et al. (2010), Discovery of an Oral Potent Selective Inhibitor of Hematopoietic Prostaglandin D Synthase (HPGDS). ACS Med. Chem. Lett. 1, 59-63; Christ et al. (2010), Development and Characterization of New Inhibitors of the Human and Mouse Hematopoietic Prostaglandin D 2 Synthases, J. Med. Chem., 53, 5536-5548; and Hohwy et al. (2008), Novel Prostaglandin D Synthase Inhibitors Generated by Fragment-Based Drug Design. J. Med. Chem., 51, 2178-2186 are also of interest.

Based on this evidence, chemical inhibitors of H-PGDS which inhibit PGD 2 formation, simultaneously inhibit the biological actions of PGD 2 and its metabolites at multiple receptors and offer the potential for therapeutic benefit in the treatment of a range of diseases where PGD 2 is considered to play a pathological role.

International Patent Applications WO2005/094805, WO2007/007778, WO2007/041634, 2008/121670, WO2008/122787, WO2009/153720, WO2009/153721, WO2010/033977, WO2010/104024, WO2011/043359, WO2011044307, WO2011/090062, Japanese Patent Application 2007-51121 and US Patent Application 2008/0146569 disclose certain H-PGDS inhibitors and their use in the treatment of diseases associated with the activity of H-PGDS.

It is an object of the invention to provide further H-PGDS inhibitors, suitably for the treatment of Muscular Dystrophy.

The invention is directed to compounds according to Formula I:

wherein R, R 1 , R 2 , R 3 , Y, Y 1 , a, X, and Z are as defined below.

Compounds of formula (I) and their pharmaceutically acceptable salts have H-PGDS activity and are believed to be of use for the treatment or prophylaxis of certain disorders.

Accordingly, in another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

In some embodiments, the pharmaceutical composition is for the treatment or prophylaxis of a disorder in which inhibition of H-PGDS is beneficial.

In a further aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention for use in therapy.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition for which an H-PGDS inhibitor is indicated.

This invention also relates to a method of treating Duchenne muscular dystrophy, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating congenital myotonia, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating muscle injury, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating muscle lacerations, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating chronic muscle strains, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating Myotonic dystrophy type I, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating myotonic dystrophy type II, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating asthma, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating chronic obstructive pulmonary disease, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating rheumatoid arthritis, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating inflammatory bowel disease, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating osteoarthritis, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating psoriasis, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating a muscle degenerative disorder, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

This invention also relates to a method of treating muscular dystrophy, which comprises administering to a subject in need thereof an effective amount of a H-PGDS inhibiting compound of Formula (I).

Also included in the present invention are methods of co-administering the presently invented H-PGDS inhibiting compounds with further active ingredients.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Duchenne muscular dystrophy.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of congenital myotonia.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of muscle injury.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of muscle lacerations.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic muscle strains.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Myotonic dystrophy type I.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of myotonic dystrophy type II.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of asthma.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic obstructive pulmonary disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of osteoarthritis.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a muscle degenerative disorder.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of muscular dystrophy.

The invention provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions in which an inhibitor of H-PGDS is indicated.

The invention further provides a method for the treatment or prophylaxis of disorders in which inhibition of H-PGDS is indicated, in a human, which comprises administering a human in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

FIG. 1 depicts the protection and acceleration of functional repair dose response curves of H-PGDS Inhibition using the compound of Example 141 following limb muscle injury in normal mice.

This invention relates to novel compounds of Formula (I):

wherein:

X is selected from: carbon and nitrogen; Y is selected from: hydrogen and CH 3 ; Y 1 is absent or CH 3 ; Z is NH or O; a is 0 or 1; R is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen; R 1 is selected from:

aryl, aryl substituted from 1 to 4 times by R a , heteroaryl, heteroaryl substituted from 1 to 4 times by R a , bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 4 times by R a ;

R 2 is selected from: O and S; R 3 is selected from:

aryl, aryl substituted from 1 to 4 times by R b , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R b , heterocycle, heterocycle substituted from 1 to 4 times by R b , heteroaryl, heteroaryl substituted from 1 to 4 times by R b , bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 4 times by R b ;

each R a is independently selected from:

fluoro, chloro, bromo, iodo, —OH, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkyloxy, —OH, C 1-4 alkyl, oxo, —COOH, —NO 2 , —NH 2 and —CN, cyano, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkyloxy, —OH, C 1-4 alkyl, oxo, —COOH, —NO 2 , —NH 2 and —CN, —C(O)OC 1-6 alkyl, and —C(O)OC 1-6 alkyl substituted 1 to 5 times by fluoro;

each R b is independently selected from:

cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , oxo, hydroxyl, cycloalkyl, cycloalkyl substituted from 1 to 4 times by R f , amino, —NHR x ,

where R x is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, and —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , —NHcycloalkyl, and —CN,

heteroaryl, heteroaryl substituted from 1 to 4 times by R f , heterocycle, heterocycle substituted from 1 to 4 times by R f , —SO 2 H, and —SO 2 C 1-6 alkyl;

each R f is independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , oxo, —OH, amino, —NHR x1 ,

where R x1 is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —OC 1-6 alkyl, —COOH, —NH 2 , and —CN,

—NR x2 R x3 ,

where R x2 and R x3 are each independently selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

nitro, and cyano, and

each R e is independently selected from:

C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , —CN, and phenyl, oxo, ═N, hydroxyl, amino, —NHR xx , or ═NR xx ,

where R xx is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro,

—NR xx1 R xx2 ,

where R xx1 and R xx2 are each independently selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

aryl, aryl substituted from 1 to 4 times by R xx3 ,

where R xx3 is selected from: fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —OC 1-5 alkyl, and —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

cycloalkyl, cycloalkyl substituted from 1 to 4 times by R xx4 ,

where R xx4 is selected from: fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —OC 1-5 alkyl, and —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN

nitro, and cyano;

or a pharmaceutically acceptable salt thereof.

Suitably in the compounds of Formula (I), X is selected from: carbon and nitrogen. Suitably in the compounds of Formula (I), X is nitrogen. Suitably in the compounds of Formula (I), X is carbon.

Suitably in the compounds of Formula (I), Y is independently selected from: hydrogen and CH 3 . Suitably in the compounds of Formula (I), Y 1 is absent or CH 3 . Suitably in the compounds of Formula (I), Y hydrogen. Suitably in the compounds of Formula (I), Y 1 is absent.

Suitably in the compounds of Formula (I), Z is NH or O. Suitably in the compounds of Formula (I), Z is NH. Suitably in the compounds of Formula (I), Z is O.

Suitably in the compounds of Formula (I), a is 0 or 1. Suitably in the compounds of Formula (I), a is 0. Suitably in the compounds of Formula (I), a is 1.

Suitably in the compounds of Formula (I), R is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen.

Suitably in the compounds of Formula (I), R 1 is selected from:

phenyl, phenyl substituted from 1 to 3 times by R a , benzothiazolyl, benzothiazolyl substituted from 1 to 3 times by R a , quinolinyl, quinolinyl substituted from 1 to 3 times by R a , thienopyridinyl, thienopyridinyl substituted from 1 to 3 times by R a , benzofuranyl, benzofuranyl substituted from 1 to 3 times by R a , quinazolinyl, quinazolinyl substituted from 1 to 3 times by R a , benzoimidazolyl, benzoimidazolyl substituted from 1 to 3 times by R a , imidazopyridinyl, imidazopyridinyl substituted from 1 to 3 times by R a , benzoisothiazolyl, and benzoisothiazolyl substituted from 1 to 3 times by R a ;

where each R a is independently selected from:

fluoro, chloro, bromo, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , and —OCHF 2 .

Suitably in the compounds of Formula (I), R 2 is selected from: O and S, suitably O. Suitably in the compounds of Formula (I), R 3 is selected from:

cyclohexyl, cyclohexyl substituted from 1 to 3 times by R b , tetrazolyl, tetrazolyl substituted from 1 to 3 times by R b , azetidinyl, azetidinyl substituted from 1 to 3 times by R b , cyclobutanyl, cyclobutanyl substituted from 1 to 3 times by R b , thiazolyl, thiazolyl substituted from 1 to 3 times by R b , oxadiazolyl, oxadiazolyl substituted from 1 to 3 times by R b , piperidinyl, piperidinyl substituted from 1 to 3 times by R b , pyrimidinyl, pyrimidinyl substituted from 1 to 3 times by R b , indolinyl, indolinyl substituted from 1 to 3 times by R b , tetrahydroquinolinyl, tetrahydroquinolinyl substituted from 1 to 3 times by R b , pyridinyl, pyridinyl substituted from 1 to 3 times by R b , tetrahydropyranyl, tetrahydropyranyl substituted from 1 to 3 times by R b , pyrrolidinyl, pyrrolidinyl substituted from 1 to 3 times by R b , spiroheptanyl, spiroheptanyl substituted from 1 to 3 times by R b , morpholinyl, morpholinyl substituted from 1 to 3 times by R b , indolinyl, indolinyl substituted from 1 to 3 times by R b , azaspiroheptanyl, azaspiroheptanyl substituted from 1 to 3 times by R b , oxazolyl, oxazolyl substituted from 1 to 3 times by R b , thiadiazolyl, thiadiazolyl substituted from 1 to 3 times by R b , triazolyl, triazolyl substituted from 1 to 3 times by R b , dihydroindenyl, dihydroindenyl substituted from 1 to 3 times by R b , 2-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane substituted from 1 to 3 times by R b , pyridazinyl, pyridazinyl substituted from 1 to 3 times by R b , pyrazinyl, pyrazinyl substituted from 1 to 3 times by R b , thiophenyl, thiophenyl substituted from 1 to 3 times by R b , tetrahydrothiophenyl, tetrahydrothiophenyl substituted from 1 to 3 times by R b , furanyl, and furanyl substituted from 1 to 3 times by R b ;

where each R b is independently selected from:

—C(OH)(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 3 , —OH cyano, —OCH 2 CH(OH)cyclopropyl, —OCH 2 C(CH 3 )(OH)cyclopropyl, —CH 2 OH, —NH 2 , —CH 2 CHF 2 , —C(CH 3 ) 3 , —NHCH(CF 3 )CH 2 OH, —CH(CH 3 )CHF 2 , —NHCH(CH 3 )CHF 2 , oxo, —CH(CH 3 )OH, —CH(OH)cyclopropyl, —C(CH 3 )(CF 3 )OH, —C(O)OCH 2 CH 3 , —C(O)cyclopropyl, —OCH 2 C(OH)(CH 3 ) 2 , —C(O)CH 3 , —OCH 2 CH 2 OCH 3 , —C(NHCH 3 )Ncyano, —NHC(O)OC(CH 3 ) 3 , —NHC(O)NHcyclohexyl, NHpyrimidinyl, —CH(CH 3 )CF 3 , —C(O)OCH 2 phenyl, —C(O)NHtetrahydropyran, —CH 2 CF 3 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , cyclopropyl, —OCH 3 , —CH 2 (chloro-methoxyphenyl), —C(O)N(CH 3 ) 2 , —NHCH(CF 3 )CH 3 , —NHC(CH 3 )(OH)CHF 2 , —C(O)NH 2 , —C(O)OH, —C(O)NH(CH 3 ), —CH(CH 3 ) 2 , —CF 3 , —C(CH 2 )CH 3 , —CH 2 C(OH)(CH 3 ) 2 , —C(O)CH 2 CH 3 , fluoro, —CH 2 C(O)CH 2 CH 3 , —CH 2 C(O)OCH 2 CH 3 , thiazolyl, thiazolyl substituted 1 or 2 times by R f , pyrimidinyl, pyrimidinyl substituted 1 or 2 times by R f , pyridinyl, pyridinyl substituted 1 or 2 times by R f , azetidinyl, azetidinyl substituted 1 or 2 times by R f , oxazolyl, oxazolyl substituted 1 or 2 times by R f , oxadiazolyl, oxadiazolyl substituted 1 or 2 times by R f , isothiazolidinyl, isothiazolidinyl substituted 1 or 2 times by R f , imidazolidinyl, imidazolidinyl substituted 1 or 2 times by R f , oxooxazolidinyl, oxooxazolidinyl substituted 1 or 2 times by R f , morpholinyl, morpholinyl substituted 1 or 2 times by R f , tetrazolyl, tetrazolyl substituted 1 or 2 times by R f , pyrazinyl, pyrazinyl substituted 1 or 2 times by R f , pyridazinyl, pyridazinyl substituted 1 or 2 times by R f , pyrazolyl, pyrazolyl substituted 1 or 2 times by R f , thiophenyl, and thiophenyl substituted 1 or 2 times by R f ; and

each R f is independently selected from:

cyano, —C(NH)OCH 3 , —C(O)NH 2 , fluoro, chloro, —C(O)NH 2 , —C(O)NHCH 3 , —CH 3 , —C(O)OCH 3 , —C(O)CH 3 , —C(O)OCH 2 CH 3 , —C(OH)(CH 3 ) 2 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 ) 2 , oxo, —OCH 3 , and —C(O)NHCH 2 CH 2 OCH 2 CH 3 .

Included in the presently invented compounds of Formula (I) are compounds of Formula

wherein:

X 1 is selected from: carbon and nitrogen; Y 10 is selected from: hydrogen and CH 3 ; Y 11 is absent or CH 3 ; Z 1 is NH or O; a 1 is 0 or 1; R 10 is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen; R 11 is selected from:

aryl, aryl substituted from 1 to 3 times by R a1 , bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 3 times by R a1 ;

R 12 is selected from: O and S; R 13 is selected from:

aryl, aryl substituted from 1 to 3 times by R b1 , cycloalkyl, cycloalkyl substituted from 1 to 3 times by R b1 , heterocycle, heterocycle substituted from 1 to 3 times by R b1 , heteroaryl, heteroaryl substituted from 1 to 3 times by R b1 , bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 3 times by R b1 ;

each R a1 is independently selected from:

fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkyloxy, —OH, oxo, and —COOH, —OC 1-6 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkyloxy, —OH, oxo, and —COOH, and —C(O)OC 1-3 alkyl;

each R b1 is independently selected from:

cyano, fluoro, chloro, C 1-6 alkyl, R e1 , —OC 1-6 alkyl, —OR e1 , oxo, hydroxyl, cycloalkyl, cycloalkyl substituted by R f1 , amino, —NHR x10 ,

where R x10 is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, and —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , —NHcycloalkyl, and —CN,

heteroaryl, heteroaryl substituted from 1 to 4 times by R f1 , heterocycle, heterocycle substituted from 1 to 4 times by R f1 , —SO 2 H, and —SO 2 C 1-6 alkyl;

each R f1 is independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e1 , oxo, —OH, amino, NHR x11 ,

where R x11 is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —OC 1-6 alkyl, —COOH, —NH 2 , and —CN,

—NR x12 R x13 ,

where R x12 and R x13 are each independently selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, and —COOH,

nitro, and cyano; and

each R e1 is independently selected from:

C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and phenyl, oxo, ═N, hydroxyl, amino, —NHR xx10 , or ═NR xx10 ,

where R xx10 is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, C 1-3 alkyl, and C 1-3 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 4 times by fluoro,

—NR xx11 R xx12 ,

where R xx11 and R xx12 are each independently selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, and —OH,

aryl, aryl substituted from 1 to 4 times by R xx13 ,

where R xx13 is selected from: fluoro, chloro, bromo, iodo, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —OC 1-3 alkyl, and —OC 1-6 alkyl substituted from 1 to 6 times by fluoro,

cycloalkyl, and cycloalkyl substituted from 1 to 4 times by R xx14 ,

where R xx14 is selected from: fluoro, chloro, bromo, iodo, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, and —OC 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

Suitably in the compounds of Formula (II), X 1 is selected from: carbon and nitrogen. Suitably in the compounds of Formula (II), X 1 is nitrogen. Suitably in the compounds of Formula (II), X 1 is carbon.

Suitably in the compounds of Formula (II), Y 10 is independently selected from: hydrogen and CH 3 . Suitably in the compounds of Formula (II), Y 11 is absent or CH 3 . Suitably in the compounds of Formula (II), Y 10 hydrogen. Suitably in the compounds of Formula (II), Y 11 is absent.

Suitably in the compounds of Formula (II), Z 1 is NH or O. Suitably in the compounds of Formula (II), Z 1 is NH. Suitably in the compounds of Formula (II), Z 1 is O.

Suitably in the compounds of Formula (II), a 1 is 0 or 1. Suitably in the compounds of Formula (II), a 1 is 0. Suitably in the compounds of Formula (II), a 1 is 1.

Suitably in the compounds of Formula (II), R 10 is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen.

Suitably in the compounds of Formula (II), R 11 is selected from:

phenyl, phenyl substituted from 1 to 3 times by R a1 , benzothiazolyl, benzothiazolyl substituted from 1 to 3 times by R a1 , quinolinyl, quinolinyl substituted from 1 to 3 times by R a1 , thienopyridinyl, thienopyridinyl substituted from 1 to 3 times by R a1 , benzofuranyl, benzofuranyl substituted from 1 to 3 times by R a1 , quinazolinyl, quinazolinyl substituted from 1 to 3 times by R a1 , benzoimidazolyl, benzoimidazolyl substituted from 1 to 3 times by R a1 , imidazopyridinyl, imidazopyridinyl substituted from 1 to 3 times by R a1 , benzoisothiazolyl, and benzoisothiazolyl substituted from 1 to 3 times by R a1 ;

where each R a1 is independently selected from:

fluoro, chloro, bromo, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , and —OCHF 2 .

Suitably in the compounds of Formula (II), R 12 is selected from: O and S, suitably O. Suitably in the compounds of Formula (II), R 13 is selected from:

cyclohexyl, cyclohexyl substituted from 1 to 3 times by R b1 , tetrazolyl, tetrazolyl substituted from 1 to 3 times by R b1 , azetidinyl, azetidinyl substituted from 1 to 3 times by R b1 , cyclobutanyl, cyclobutanyl substituted from 1 to 3 times by R b1 , thiazolyl, thiazolyl substituted from 1 to 3 times by R b1 , oxadiazolyl, oxadiazolyl substituted from 1 to 3 times by R b1 , piperidinyl, piperidinyl substituted from 1 to 3 times by R b1 , pyrimidinyl, pyrimidinyl substituted from 1 to 3 times by R b1 , indolinyl, indolinyl substituted from 1 to 3 times by R b1 , tetrahydroquinolinyl, tetrahydroquinolinyl substituted from 1 to 3 times by R b1 , pyridinyl, pyridinyl substituted from 1 to 3 times by R b1 , tetrahydropyranyl, tetrahydropyranyl substituted from 1 to 3 times by R b1 , pyrrolidinyl, pyrrolidinyl substituted from 1 to 3 times by R b1 , spiroheptanyl, spiroheptanyl substituted from 1 to 3 times by R b1 , morpholinyl, morpholinyl substituted from 1 to 3 times by R b1 , indolinyl, indolinyl substituted from 1 to 3 times by R b1 , azaspiroheptanyl, azaspiroheptanyl substituted from 1 to 3 times by R b1 , oxazolyl, oxazolyl substituted from 1 to 3 times by R b1 , thiadiazolyl, thiadiazolyl substituted from 1 to 3 times by R b1 , triazolyl, triazolyl substituted from 1 to 3 times by R b1 dihydroindenyl, dihydroindenyl substituted from 1 to 3 times by R b1 , 2-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane substituted from 1 to 3 times by R b1 , pyridazinyl, pyridazinyl substituted from 1 to 3 times by R b1 , pyrazinyl, pyrazinyl substituted from 1 to 3 times by R b1 , thiophenyl, thiophenyl substituted from 1 to 3 times by R b1 , tetrahydrothiophenyl, tetrahydrothiophenyl substituted from 1 to 3 times by R b1 , furanyl, and furanyl substituted from 1 to 3 times by R b1 ;

where each R b1 is independently selected from:

—C(OH)(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 3 , —OH cyano, —OCH 2 CH(OH)cyclopropyl, —OCH 2 C(CH 3 )(OH)cyclopropyl, —CH 2 OH, —NH 2 , —CH 2 CHF 2 , —C(CH 3 ) 3 , —NHCH(CF 3 )CH 2 OH, —CH(CH 3 )CHF 2 , —NHCH(CH 3 )CHF 2 , oxo, —CH(CH 3 )OH, —CH(OH)cyclopropyl, —C(CH 3 )(CF 3 )OH, —C(O)OCH 2 CH 3 , —C(O)cyclopropyl, —OCH 2 C(OH)(CH 3 ) 2 , —C(O)CH 3 , —OCH 2 CH 2 OCH 3 , —C(NHCH 3 )Ncyano, —NHC(O)OC(CH 3 ) 3 , —NHC(O)NHcyclohexyl, NHpyrimidinyl, —CH(CH 3 )CF 3 , —C(O)OCH 2 phenyl, —C(O)NHtetrahydropyran, —CH 2 CF 3 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , cyclopropyl, —OCH 3 , —CH 2 (chloro-methoxyphenyl), —C(O)N(CH 3 ) 2 , —NHCH(CF 3 )CH 3 , —NHC(CH 3 )(OH)CHF 2 , —C(O)NH 2 , —C(O)OH, —C(O)NH(CH 3 ), —CH(CH 3 ) 2 , —CF 3 , —C(CH 2 )CH 3 , —CH 2 C(OH)(CH 3 ) 2 , —C(O)CH 2 CH 3 , fluoro, —CH 2 C(O)CH 2 CH 3 , —CH 2 C(O)OCH 2 CH 3 , thiazolyl, thiazolyl substituted 1 or 2 times by R f1 , pyrimidinyl, pyrimidinyl substituted 1 or 2 times by R f1 , pyridinyl, pyridinyl substituted 1 or 2 times by R f1 , azetidinyl, azetidinyl substituted 1 or 2 times by R f1 , oxazolyl, oxazolyl substituted 1 or 2 times by R f1 , oxadiazolyl, oxadiazolyl substituted 1 or 2 times by R f1 , isothiazolidinyl, isothiazolidinyl substituted 1 or 2 times by R f1 , imidazolidinyl, imidazolidinyl substituted 1 or 2 times by R f1 , oxooxazolidinyl, oxooxazolidinyl substituted 1 or 2 times by R f1 , morpholinyl, morpholinyl substituted 1 or 2 times by R f1 , tetrazolyl, tetrazolyl substituted 1 or 2 times by R f1 , pyrazinyl, pyrazinyl substituted 1 or 2 times by R f1 , pyridazinyl, pyridazinyl substituted 1 or 2 times by R f1 , pyrazolyl, pyrazolyl substituted 1 or 2 times by R f1 , thiophenyl, and thiophenyl substituted 1 or 2 times by R f1 ; and

each R f1 is independently selected from:

cyano, —C(NH)OCH 3 , —C(O)NH 2 , fluoro, chloro, —C(O)NH 2 , —C(O)NHCH 3 , —CH 3 , —C(O)OCH 3 , —C(O)CH 3 , —C(O)OCH 2 CH 3 , —C(OH)(CH 3 ) 2 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 ) 2 , oxo, —OCH 3 , and —C(O)NHCH 2 CH 2 OCH 2 CH 3 .

Included in the presently invented compounds of Formula (I) are compounds of Formula (III):

wherein:

X 2 is selected from: carbon and nitrogen; Y 20 is selected from: hydrogen and CH 3 ; Y 21 is absent or CH 3 ; Z 2 is NH or O; a 2 is 0 or 1; R 20 is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen; R 21 is selected from: aryl, aryl substituted from 1 to 3 times by R a2 , bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 3 times by R a2 ; R 22 is selected from: O and S; R 23 is selected from:

aryl, aryl substituted from 1 to 3 times by R b2 , cycloalkyl, cycloalkyl substituted from 1 to 3 times by R b2 , heterocycle, heterocycle substituted from 1 to 3 times by R b2 , heteroaryl, heteroaryl substituted from 1 to 3 times by R b2 , bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 3 times by R b2 ;

each R a2 is independently selected from:

fluoro, chloro, bromo, iodo, C 1-3 alkyl, C 1-3 alkyl substituted 1 to 4 times by fluoro, —OC 1-4 alkyl, and —OC 1-4 alkyl substituted 1 to 4 times by fluoro;

each R b2 is independently selected from:

cyano, C 1-6 alkyl, R e2 , —OC 1-4 alkyl, —OR e2 , oxo, hydroxyl, cycloalkyl, amino, —NHR x20 ,

where R x20 is selected from heteroaryl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted 1 to 4 times by fluoro, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-6 alkyl, —NH 2 , and —NHcycloalkyl,

heteroaryl, heteroaryl substituted from 1 to 3 times by R f2 , heterocycle, heterocycle substituted from 1 to 3 times by R f2 , —SO 2 H, and —SO 2 C 1-6 alkyl;

each R f2 is independently selected from:

fluoro, chloro, C 1-4 alkyl, R e2 , oxo, amino, —NHR x21 ,

where R x21 is selected from C 1-4 alkyl, and C 1-4 alkyl substituted by —OC 1-6 alkyl,

—NR x22 R x23 ,

where R x22 and R x23 are each independently selected from: C 1-4 alkyl, and C 1-6 alkyl substituted 1 to 4 times by fluoro, and

cyano; and

each R e2 is independently selected from:

C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from:

fluoro, —OC 1-4 alkyl, —OC 1-4 alkyl substituted by phenyl, oxo, ═N, hydroxyl, amino, —NHR xx20 , or ═NR xx20 ,

where R xx20 is selected from cyano, C 1-3 alkyl, and C 1-3 alkyl by —OC 1-5 alkyl,

—NR xx21 R xx22 ,

where R xx21 and R xx22 are each independently selected from: C 1-4 alkyl,

aryl, aryl substituted by —OC 1-3 alkyl, and cycloalkyl;

or a pharmaceutically acceptable salt thereof.

Suitably in the compounds of Formula (III), X 2 is selected from: carbon and nitrogen. Suitably in the compounds of Formula (III), X 2 is nitrogen. Suitably in the compounds of Formula (III), X 2 is carbon.

Suitably in the compounds of Formula (III), Y 20 is independently selected from: hydrogen and CH 3 . Suitably in the compounds of Formula (III), Y 21 is absent or CH 3 . Suitably in the compounds of Formula (III), Y 20 hydrogen. Suitably in the compounds of Formula (III), Y 21 is absent.

Suitably in the compounds of Formula (III), Z 2 is NH or O. Suitably in the compounds of Formula (III), Z 2 is NH. Suitably in the compounds of Formula (III), Z 2 is O.

Suitably in the compounds of Formula (III), a 2 is 0 or 1. Suitably in the compounds of Formula (III), a 2 is 0. Suitably in the compounds of Formula (III), a 2 is 1.

Suitably in the compounds of Formula (III), R 00 is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen.

Suitably in the compounds of Formula (III), R 21 is selected from:

phenyl, phenyl substituted from 1 to 3 times by R a2 , benzothiazolyl, benzothiazolyl substituted from 1 to 3 times by R a2 , quinolinyl, quinolinyl substituted from 1 to 3 times by R a2 , thienopyridinyl, thienopyridinyl substituted from 1 to 3 times by R a2 , benzofuranyl, benzofuranyl substituted from 1 to 3 times by R a2 , quinazolinyl, quinazolinyl substituted from 1 to 3 times by R a2 , benzoimidazolyl, benzoimidazolyl substituted from 1 to 3 times by R a2 , imidazopyridinyl, imidazopyridinyl substituted from 1 to 3 times by R a2 , benzoisothiazolyl, and benzoisothiazolyl substituted from 1 to 3 times by R a2 ;

where each R a2 is independently selected from:

fluoro, chloro, bromo, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , and —OCHF 2 .

Suitably in the compounds of Formula (III), R 22 is selected from: O and S, suitably O. Suitably in the compounds of Formula (III), R 23 is selected from:

cyclohexyl, cyclohexyl substituted from 1 to 3 times by R b2 , tetrazolyl, tetrazolyl substituted from 1 to 3 times by R b2 , azetidinyl, azetidinyl substituted from 1 to 3 times by R b2 , cyclobutanyl, cyclobutanyl substituted from 1 to 3 times by R b2 , thiazolyl, thiazolyl substituted from 1 to 3 times by R b2 , oxadiazolyl, oxadiazolyl substituted from 1 to 3 times by R b2 , piperidinyl, piperidinyl substituted from 1 to 3 times by R b2 , pyrimidinyl, pyrimidinyl substituted from 1 to 3 times by R b2 , indolinyl, indolinyl substituted from 1 to 3 times by R b2 , tetrahydroquinolinyl, tetrahydroquinolinyl substituted from 1 to 3 times by R b2 , pyridinyl, pyridinyl substituted from 1 to 3 times by R b2 , tetrahydropyranyl, tetrahydropyranyl substituted from 1 to 3 times by R b2 , pyrrolidinyl, pyrrolidinyl substituted from 1 to 3 times by R b2 , spiroheptanyl, spiroheptanyl substituted from 1 to 3 times by R b2 , morpholinyl, morpholinyl substituted from 1 to 3 times by R b2 , indolinyl, indolinyl substituted from 1 to 3 times by R b2 , azaspiroheptanyl, azaspiroheptanyl substituted from 1 to 3 times by R b2 , oxazolyl, oxazolyl substituted from 1 to 3 times by R b2 , thiadiazolyl, thiadiazolyl substituted from 1 to 3 times by R b2 , triazolyl, triazolyl substituted from 1 to 3 times by R b2 , dihydroindenyl, dihydroindenyl substituted from 1 to 3 times by R b2 , 2-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane substituted from 1 to 3 times by R b2 , pyridazinyl, pyridazinyl substituted from 1 to 3 times by R b2 , pyrazinyl, pyrazinyl substituted from 1 to 3 times by R b2 , thiophenyl, thiophenyl substituted from 1 to 3 times by R b2 , tetrahydrothiophenyl, tetrahydrothiophenyl substituted from 1 to 3 times by R b2 , furanyl, and furanyl substituted from 1 to 3 times by R b2 ;

where each R b2 is independently selected from:

—C(OH)(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 3 , —OH, cyano, —OCH 2 CH(OH)cyclopropyl, —OCH 2 C(CH 3 )(OH)cyclopropyl, —CH 2 OH, —NH 2 , —CH 2 CHF 2 , —C(CH 3 ) 3 , —NHCH(CF 3 )CH 2 OH, —CH(CH 3 )CHF 2 , —NHCH(CH 3 )CHF 2 , oxo, —CH(CH 3 )OH, —CH(OH)cyclopropyl, —C(CH 3 )(CF 3 )OH, —C(O)OCH 2 CH 3 , —C(O)cyclopropyl, —OCH 2 C(OH)(CH 3 ) 2 , —C(O)CH 3 , —OCH 2 CH 2 OCH 3 , —C(NHCH 3 )Ncyano, —NHC(O)OC(CH 3 ) 3 , —NHC(O)NHcyclohexyl, NHpyrimidinyl, —CH(CH 3 )CF 3 , —C(O)OCH 2 phenyl, —C(O)NHtetrahydropyran, —CH 2 CF 3 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , cyclopropyl, —OCH 3 , —CH 2 (chloro-methoxyphenyl), —C(O)N(CH 3 ) 2 , —NHCH(CF 3 )CH 3 , —NHC(CH 3 )(OH)CHF 2 , —C(O)NH 2 , —C(O)OH, —C(O)NH(CH 3 ), —CH(CH 3 ) 2 , —CF 3 , —C(CH 2 )CH 3 , —CH 2 C(OH)(CH 3 ) 2 , —C(O)CH 2 CH 3 , fluoro, —CH 2 C(O)CH 2 CH 3 , —CH 2 C(O)OCH 2 CH 3 , thiazolyl, thiazolyl substituted 1 or 2 times by R f2 , pyrimidinyl, pyrimidinyl substituted 1 or 2 times by R f2 , pyridinyl, pyridinyl substituted 1 or 2 times by R f2 , azetidinyl, azetidinyl substituted 1 or 2 times by R f2 , oxazolyl, oxazolyl substituted 1 or 2 times by R f2 , oxadiazolyl, oxadiazolyl substituted 1 or 2 times by R f2 , isothiazolidinyl, isothiazolidinyl substituted 1 or 2 times by R f2 , imidazolidinyl, imidazolidinyl substituted 1 or 2 times by R f2 , oxooxazolidinyl, oxooxazolidinyl substituted 1 or 2 times by R f2 , morpholinyl, morpholinyl substituted 1 or 2 times by R f2 , tetrazolyl, tetrazolyl substituted 1 or 2 times by R f2 , pyrazinyl, pyrazinyl substituted 1 or 2 times by R f2 , pyridazinyl, pyridazinyl substituted 1 or 2 times by R f2 , pyrazolyl, pyrazolyl substituted 1 or 2 times by R f2 , thiophenyl, and thiophenyl substituted 1 or 2 times by R f2 ; and

each R f2 is independently selected from:

cyano, —C(NH)OCH 3 , —C(O)NH 2 , fluoro, chloro, —C(O)NH 2 , —C(O)NHCH 3 , —CH 3 , —C(O)OCH 3 , —C(O)CH 3 , —C(O)OCH 2 CH 3 , —C(OH)(CH 3 ) 2 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 ) 2 , oxo, —OCH 3 , and —C(O)NHCH 2 CH 2 OCH 2 CH 3 .

Included in the presently invented compounds of Formula (I) are compounds of Formula (IV):

wherein:

X 3 is selected from: carbon and nitrogen; Y 30 is selected from: hydrogen and CH 3 ; Y 31 is absent or CH 3 ; Z 3 is NH or O; a 3 is 0 or 1; R 30 is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen; R 31 is selected from:

phenyl, phenyl substituted from 1 to 3 times by R a3 , benzothiazolyl, benzothiazolyl substituted from 1 to 3 times by R a3 , quinolinyl, quinolinyl substituted from 1 to 3 times by R a3 , thienopyridinyl, thienopyridinyl substituted from 1 to 3 times by R a3 , benzofuranyl, benzofuranyl substituted from 1 to 3 times by R a3 , quinazolinyl, quinazolinyl substituted from 1 to 3 times by R a3 , benzoimidazolyl, benzoimidazolyl substituted from 1 to 3 times by R a3 , imidazopyridinyl, imidazopyridinyl substituted from 1 to 3 times by R a3 , benzoisothiazolyl, and benzoisothiazolyl substituted from 1 to 3 times by R a3 ;

R 32 is selected from: O and S; R 33 is selected from:

cyclohexyl, cyclohexyl substituted from 1 to 3 times by R b3 , tetrazolyl, tetrazolyl substituted from 1 to 3 times by R b3 , azetidinyl, azetidinyl substituted from 1 to 3 times by R b3 , cyclobutanyl, cyclobutanyl substituted from 1 to 3 times by R b3 , thiazolyl, thiazolyl substituted from 1 to 3 times by R b3 , oxadiazolyl, oxadiazolyl substituted from 1 to 3 times by R b3 , piperidinyl, piperidinyl substituted from 1 to 3 times by R b3 , pyrimidinyl, pyrimidinyl substituted from 1 to 3 times by R b3 , indolinyl, indolinyl substituted from 1 to 3 times by R b3 , tetrahydroquinolinyl, tetrahydroquinolinyl substituted from 1 to 3 times by R b3 , pyridinyl, pyridinyl substituted from 1 to 3 times by R b3 , tetrahydropyranyl, tetrahydropyranyl substituted from 1 to 3 times by R b3 , pyrrolidinyl, pyrrolidinyl substituted from 1 to 3 times by R b3 , spiroheptanyl, spiroheptanyl substituted from 1 to 3 times by R b3 , morpholinyl, morpholinyl substituted from 1 to 3 times by R b3 , indolinyl, indolinyl substituted from 1 to 3 times by R b3 , azaspiroheptanyl, azaspiroheptanyl substituted from 1 to 3 times by R b3 , oxazolyl, xazolyl substituted from 1 to 3 times by R b3 , thiadiazolyl, thiadiazolyl substituted from 1 to 3 times by R b3 , triazolyl, triazolyl substituted from 1 to 3 times by R b3 , dihydroindenyl, dihydroindenyl substituted from 1 to 3 times by R b3 , 2-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane substituted from 1 to 3 times by R b3 , pyridazinyl, pyridazinyl substituted from 1 to 3 times by R b3 , pyrazinyl, pyrazinyl substituted from 1 to 3 times by R b3 , thiophenyl, thiophenyl substituted from 1 to 3 times by R b3 , tetrahydrothiophenyl, tetrahydrothiophenyl substituted from 1 to 3 times by R b3 , furanyl, and furanyl substituted from 1 to 3 times by R b3 ;

each R a3 is independently selected from:

fluoro, chloro, bromo, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , and —OCHF 2 ;

each R b3 is independently selected from:

—C(OH)(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 3 , —OH cyano, —OCH 2 CH(OH)cyclopropyl, —OCH 2 C(CH 3 )(OH)cyclopropyl, —CH 2 OH, —NH 2 , —CH 2 CHF 2 , —C(CH 3 ) 3 , —NHCH(CF 3 )CH 2 OH, —CH(CH 3 )CHF 2 , —NHCH(CH 3 )CHF 2 , oxo, —CH(CH 3 )OH, —CH(OH)cyclopropyl, —C(CH 3 )(CF 3 )OH, —C(O)OCH 2 CH 3 , —C(O)cyclopropyl, —OCH 2 C(OH)(CH 3 ) 2 , —C(O)CH 3 , —OCH 2 CH 2 OCH 3 , —C(NHCH 3 )Ncyano, —NHC(O)OC(CH 3 ) 3 , —NHC(O)NHcyclohexyl, NHpyrimidinyl, —CH(CH 3 )CF 3 , —C(O)OCH 2 phenyl, —C(O)NHtetrahydropyran, —CH 2 CF 3 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , cyclopropyl, —OCH 3 , —CH 2 (chloro-methoxyphenyl), —C(O)N(CH 3 ) 2 , —NHCH(CF 3 )CH 3 , —NHC(CH 3 )(OH)CHF 2 , —C(O)NH 2 , —C(O)OH, —C(O)NH(CH 3 ), —CH(CH 3 ) 2 , —CF 3 , —C(CH 2 )CH 3 , —CH 2 C(OH)(CH 3 ) 2 , —C(O)CH 2 CH 3 , fluoro, —CH 2 C(O)CH 2 CH 3 , —CH 2 C(O)OCH 2 CH 3 , thiazolyl, thiazolyl substituted 1 or 2 times by R f3 , pyrimidinyl, pyrimidinyl substituted 1 or 2 times by R f3 , pyridinyl, pyridinyl substituted 1 or 2 times by R f3 , azetidinyl, azetidinyl substituted 1 or 2 times by R f3 , oxazolyl, oxazolyl substituted 1 or 2 times by R f3 , oxadiazolyl, oxadiazolyl substituted 1 or 2 times by R f3 , isothiazolidinyl, isothiazolidinyl substituted 1 or 2 times by R f3 , imidazolidinyl, imidazolidinyl substituted 1 or 2 times by R f3 , oxooxazolidinyl, oxooxazolidinyl substituted 1 or 2 times by R f3 , morpholinyl, morpholinyl substituted 1 or 2 times by R f3 , tetrazolyl, tetrazolyl substituted 1 or 2 times by R f3 , pyrazinyl, pyrazinyl substituted 1 or 2 times by R f3 , pyridazinyl, pyridazinyl substituted 1 or 2 times by R f3 , pyrazolyl, pyrazolyl substituted 1 or 2 times by R f3 , thiophenyl, and thiophenyl substituted 1 or 2 times by R f3 ; and

each R f3 is independently selected from:

cyano, —C(NH)OCH 3 , —C(O)NH 2 , fluoro, chloro, —C(O)NH 2 , —C(O)NHCH 3 , —CH 3 , —C(O)OCH 3 , —C(O)CH 3 , —C(O)OCH 2 CH 3 , —C(OH)(CH 3 ) 2 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 ) 2 , oxo, —OCH 3 , and —C(O)NHCH 2 CH 2 OCH 2 CH 3 ;

or a pharmaceutically acceptable salt thereof.

Suitably in the compounds of Formula (IV), X 3 is selected from: carbon and nitrogen. Suitably in the compounds of Formula (IV), X 3 is nitrogen. Suitably in the compounds of Formula (IV), X 3 is carbon.

Suitably in the compounds of Formula (IV), Y 30 is independently selected from: hydrogen and CH 3 . Suitably in the compounds of Formula (IV), Y 31 is absent or CH 3 . Suitably in the compounds of Formula (IV), Y 30 hydrogen. Suitably in the compounds of Formula (IV), Y 31 is absent.

Suitably in the compounds of Formula (IV), Z 3 is NH or O. Suitably in the compounds of Formula (IV), Z 3 is NH. Suitably in the compounds of Formula (IV), Z 3 is O.

Suitably in the compounds of Formula (IV), a 3 is 0 or 1. Suitably in the compounds of Formula (IV), a 3 is 0. Suitably in the compounds of Formula (IV), a 3 is 1.

Suitably in the compounds of Formula (IV), R 30 is selected from: O, NH, CH 2 and C 1 alkyl substituted by halogen.

Suitably in the compounds of Formula (IV), R 31 is selected from:

phenyl, phenyl substituted from 1 to 3 times by R a3 , benzothiazolyl, benzothiazolyl substituted from 1 to 3 times by R a3 , quinolinyl, quinolinyl substituted from 1 to 3 times by R a3 , thienopyridinyl, thienopyridinyl substituted from 1 to 3 times by R a3 , benzofuranyl, benzofuranyl substituted from 1 to 3 times by R a3 , quinazolinyl, quinazolinyl substituted from 1 to 3 times by R a3 , benzoimidazolyl, benzoimidazolyl substituted from 1 to 3 times by R a3 , imidazopyridinyl, imidazopyridinyl substituted from 1 to 3 times by R a3 , benzoisothiazolyl, and benzoisothiazolyl substituted from 1 to 3 times by R a3 ;

where each R a3 is independently selected from:

fluoro, chloro, bromo, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , and —OCHF 2 .

Suitably in the compounds of Formula (IV), R 32 is selected from: O and S, suitably O. Suitably in the compounds of Formula (IV), R 33 is selected from:

cyclohexyl, cyclohexyl substituted from 1 to 3 times by R b3 , tetrazolyl, tetrazolyl substituted from 1 to 3 times by R b3 , azetidinyl, azetidinyl substituted from 1 to 3 times by R b3 , cyclobutanyl, cyclobutanyl substituted from 1 to 3 times by R b3 , thiazolyl, thiazolyl substituted from 1 to 3 times by R b3 , oxadiazolyl, oxadiazolyl substituted from 1 to 3 times by R b3 , piperidinyl, piperidinyl substituted from 1 to 3 times by R b3 , pyrimidinyl, pyrimidinyl substituted from 1 to 3 times by R b3 , indolinyl, indolinyl substituted from 1 to 3 times by R b3 , tetrahydroquinolinyl, tetrahydroquinolinyl substituted from 1 to 3 times by R b3 , pyridinyl, pyridinyl substituted from 1 to 3 times by R b3 , tetrahydropyranyl, tetrahydropyranyl substituted from 1 to 3 times by R b3 , pyrrolidinyl, pyrrolidinyl substituted from 1 to 3 times by R b3 , spiroheptanyl, spiroheptanyl substituted from 1 to 3 times by R b3 , morpholinyl, morpholinyl substituted from 1 to 3 times by R b3 , indolinyl, indolinyl substituted from 1 to 3 times by R b3 , azaspiroheptanyl, azaspiroheptanyl substituted from 1 to 3 times by R b3 , oxazolyl, oxazolyl substituted from 1 to 3 times by R b3 , thiadiazolyl, thiadiazolyl substituted from 1 to 3 times by R b3 , triazolyl, triazolyl substituted from 1 to 3 times by R b3 , dihydroindenyl, dihydroindenyl substituted from 1 to 3 times by R b3 , 2-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane substituted from 1 to 3 times by R b3 , pyridazinyl, pyridazinyl substituted from 1 to 3 times by R b3 , pyrazinyl, pyrazinyl substituted from 1 to 3 times by R b3 , thiophenyl, thiophenyl substituted from 1 to 3 times by R b3 , tetrahydrothiophenyl, tetrahydrothiophenyl substituted from 1 to 3 times by R b3 , furanyl, and furanyl substituted from 1 to 3 times by R b3 ;

where each R b3 is independently selected from:

—C(OH)(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 3 , —OH cyano, —OCH 2 CH(OH)cyclopropyl, —OCH 2 C(CH 3 )(OH)cyclopropyl, —CH 2 OH, —NH 2 , —CH 2 CHF 2 , —C(CH 3 ) 3 , —NHCH(CF 3 )CH 2 OH, —CH(CH 3 )CHF 2 , —NHCH(CH 3 )CHF 2 , oxo, —CH(CH 3 )OH, —CH(OH)cyclopropyl, —C(CH 3 )(CF 3 )OH, —C(O)OCH 2 CH 3 , —C(O)cyclopropyl, —OCH 2 C(OH)(CH 3 ) 2 , —C(O)CH 3 , —OCH 2 CH 2 OCH 3 , —C(NHCH 3 )Ncyano, —NHC(O)OC(CH 3 ) 3 , —NHC(O)NHcyclohexyl, NHpyrimidinyl, —CH(CH 3 )CF 3 , —C(O)OCH 2 phenyl, —C(O)NHtetrahydropyran, —CH 2 CF 3 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , cyclopropyl, —OCH 3 , —CH 2 (chloro-methoxyphenyl), —C(O)N(CH 3 ) 2 , —NHCH(CF 3 )CH 3 , —NHC(CH 3 )(OH)CHF 2 , —C(O)NH 2 , —C(O)OH, —C(O)NH(CH 3 ), —CH(CH 3 ) 2 , —CF 3 , —C(CH 2 )CH 3 , —CH 2 C(OH)(CH 3 ) 2 , —C(O)CH 2 CH 3 , fluoro, —CH 2 C(O)CH 2 CH 3 , —CH 2 C(O)OCH 2 CH 3 , thiazolyl, thiazolyl substituted 1 or 2 times by R f3 , pyrimidinyl, pyrimidinyl substituted 1 or 2 times by R f3 , pyridinyl, pyridinyl substituted 1 or 2 times by R f3 , azetidinyl, azetidinyl substituted 1 or 2 times by R f3 , oxazolyl, oxazolyl substituted 1 or 2 times by R f3 , oxadiazolyl, oxadiazolyl substituted 1 or 2 times by R f3 , isothiazolidinyl, isothiazolidinyl substituted 1 or 2 times by R f3 , imidazolidinyl, imidazolidinyl substituted 1 or 2 times by R f3 , oxooxazolidinyl, oxooxazolidinyl substituted 1 or 2 times by R f3 , morpholinyl, morpholinyl substituted 1 or 2 times by R f3 , tetrazolyl, tetrazolyl substituted 1 or 2 times by R f3 , pyrazinyl, pyrazinyl substituted 1 or 2 times by R f3 , pyridazinyl, pyridazinyl substituted 1 or 2 times by R f3 , pyrazolyl, pyrazolyl substituted 1 or 2 times by R f3 , thiophenyl, and thiophenyl substituted 1 or 2 times by R f3 ; and

each R f3 is independently selected from:

cyano, —C(NH)OCH 3 , —C(O)NH 2 , fluoro, chloro, —C(O)NH 2 , —C(O)NHCH 3 , —CH 3 , —C(O)OCH 3 , —C(O)CH 3 , —C(O)OCH 2 CH 3 , —C(OH)(CH 3 ) 2 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 ) 2 , oxo, —OCH 3 , and —C(O)NHCH 2 CH 2 OCH 2 CH 3 .

Included in the presently invented compounds of Formula (I) are:

3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carboxamide; (trans)-N-(1-Butyl-1H-tetrazol-5-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(1-methyl-1H-tetrazol-5-yl)cyclobutanecarboxamide; (trans)-N-(1-(5-Cyanothiazol-2-yl)azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; Methyl 2-(3-((trans)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)azetidin-1-yl)thiazole-5-carbimidate; 2-(3-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)azetidin-1-yl)thiazole-5-carboxamide; 2-(3-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)azetidin-1-yl)pyrimidine-4-carboxamide; (trans)-N-(1-(4-Cyanopyrimidin-2-yl)azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-N-(1-(2-Chloropyrimidin-4-yl)azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-N-(1-(4-Chloropyrimidin-2-yl)azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic (trans)-N-((trans)-4-(2-Cyclopropyl-2-hydroxyethoxy)cyclohexyl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-(pyrimidin-2-ylamino)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-N-((trans)-4-(2-Cyclopropyl-2-hydroxypropoxy)cyclohexyl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(5-(hydroxymethyl)thiazol-2-yl)cyclobutanecarboxamide; (trans)-(2-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)thiazol-4-yl)methyl3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylate; (trans)-(2-Aminothiazol-4-yl)methyl3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylate; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(4-(hydroxymethyl)thiazol-2-yl)cyclobutanecarboxamide; (trans)-N-(1-(2,2-Difluoroethyl)azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-N-(5-(tert-Butyl)-1,3,4-oxadiazol-2-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(1-(pyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(1-(pyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-N-((trans)-4-(3,3-Difluoroazetidin-1-yl)cyclohexyl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-(((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(1-(1,1-difluoropropan-2-yl)piperidin-4-yl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(pyrimidin-5-yl)cyclobutanecarboxamide; Racemic (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-((1,1-difluoropropan-2-yl)amino)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(2-oxoindolin-1-yl)cyclobutanecarboxamide; Racemic (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)cyclobutanecarboxamide; Racemic (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(trans)-4-(1-hydroxyethyl)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-N-((trans)-4-(Cyclopropyl(hydroxy)methyl)cyclohexyl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; Racemic (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-hydroxy-4-methylcyclohexyl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-3-hydroxy-3-methylcyclobutyl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((cis)-3-hydroxy-3-methylcyclobutyl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-(3-hydroxy-3-methylcyclobutyl)cyclobutanecarboxamide; Ethyl 2-((trans)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)thiazole-4-carboxylate; (trans)-N-(4-(Cyclopropanecarbonyl)thiazol-2-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-(2-hydroxy-2-methylpropoxy)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide; 6-(3-((trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)nicotinamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-cyanopyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; 6-(3-((trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)-N-methylnicotinamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-((1,1-difluoropropan-2-yl)amino)cyclohexyl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-7-yloxy)-N-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-7-yloxy)-N-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Methyl 2-(3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)oxazole-4-carboxylate; Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-((1,1-difluoropropan-2-yl)amino)cyclohexyl)cyclobutanecarboxamide; (trans)-N-(1-(4-Acetyloxazol-2-yl)azetidin-3-yl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide; Ethyl 2-(3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)oxazole-5-carboxylate; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2-methylpyrimidin-4-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(4-cyanopyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-methoxyethoxy)cyclohexyl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-methoxyethoxy)cyclohexyhazetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2-chloropyrimidin-4-yl)azetidin-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; N-(4-Acetylthiazol-2-yl)-3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(pyridin-4-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-cyclohexylazetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-((E)-N′-cyano-N-methylcarbamimidoyl)azetidin-3-yl)cyclobutanecarboxamide; tert-Butyl ((trans)-3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)cyclobutyl)carbamate; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-3-(3-cyclohexylureido)cyclobutyl)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2-chloropyrimidin-4-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2-(isopropylamino)pyrimidin-4-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-cyanothiazol-2-yl)azetidin-3-yl)cyclobutanecarboxamide; 2-(3-((trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)thiazole-5-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2-((2-methoxyethyl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-3-(pyrimidin-2-ylamino)cyclobutyl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(4-chloropyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(4-(dimethylamino)pyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2-(dimethylamino)pyrimidin-4-yl)azetidin-3-yl)cyclobutanecarboxamide; 2-(3-((trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)pyrimidine-4-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(4-cyanopyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyridin-2-yl)pyrrolidin-3-yl)cyclobutanecarboxamide; Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(6-(2-hydroxypropan-2-yl)spiro[3.3]heptan-2-yl)cyclobutanecarboxamide; Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)azetidine-1-carboxamide; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyridin-2-yl)pyrrolidin-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyridin-2-yl)piperidin-4-yl)azetidine-1-carboxamide; Benzyl 4-(3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)piperidine-1-carboxylate; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-(tetrahydro-2H-pyran-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-1-carboxamide; Racemic N-(1-Acetylpiperidin-3-yl)-3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamide; Racemic Methyl 3-(3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)piperidine-1-carboxylate; Racemic Methyl 2-((3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)methyl)morpholine-4-carboxylate; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carbothioamide; tert-Butyl 4-(3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)piperidine-1-carboxylate; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(methylsulfonyl)piperidin-4-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(4-(methylsulfonyl)cyclohexyl)azetidine-1-carboxamide; (S)-3-(Benzo[d]thiazol-4-yloxy)-N-(2-oxopyrrolidin-3-yl)azetidine-1-carboxamide; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-cyclopropyl-2-hydroxypropoxy)cyclohexyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-oxooxazolidin-3-yl)cyclohexyl)azetidine-1-carboxamide; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-hydroxy-4-methylcyclohexyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxy-2-methylpropoxy)cyclohexyhazetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyrimidin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypro pan-2-yl)cyclohexyl)cyclobutanecarboxamide; 6-(3-((trans)-3-(6-Fluorobenzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)nicotinamide; 2-(3-((trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)cyclobutanecarboxamido)azetidin-1-yl)-5-methylpyridine 1-oxide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-(hydroxymethyl)pyrimidin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-(hydroxymethyl)pyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-4-(2-methoxyethoxy)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(6-(2-hydroxypropan-2-yl)spiro[3.3]heptan-2-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)cyclobutanecarboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)azetidine-1-carboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic (trans)-N-((trans)-4-((1,1-Difluoropropan-2-yl)amino)cyclohexyl)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)cyclobutanecarboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(2-methylpyrimidin-4-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(2-methylpyrimidin-4-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((cis)-4-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)azetidine-1-carboxamide; Racemic (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((cis)-4-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-4-((1,1,1-trifluoro-3-hydroxypropan-2-yl) amino)cyclohexyl)cyclobutanecarboxamide; Racemic 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)azetidine-1-carboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-4-(2-methoxyethoxy)cyclohexyl)azetidine-1-carboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(pyrimidin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; N-(1-(2-Chloropyrimidin-4-yl)azetidin-3-yl)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((cis)-3-hydroxy-3-methylcyclobutyl)cyclobutanecarboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(pyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(pyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; N-(1-(4-Cyanopyridin-2-yl)azetidin-3-yl)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(pyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(4-cyclopropylthiazol-2-yl)cyclobutanecarboxamide; Racemic (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carboxamide; Racemic N-((trans)-4-((1,1-Difluoropropan-2-yl)amino)cyclohexyl)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxamide; Racemic tert-Butyl 3-((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)pyrrolidine-1-carboxylate; Racemic (trans)-N-(1-(5-Cyanothiazol-2-yl)pyrrolidin-3-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; Racemic (trans)-N-(1-(4-Cyanopyridin-2-yl)pyrrolidin-3-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(indolin-1-yl)cyclobutanecarboxamide; (trans)-N-(1-(5-Cyanothiazol-2-yl)azetidin-3-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-N-(2-(4-Cyanopyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-N-(1-(4-Cyanopyridin-2-yl)azetidin-3-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-((trans)-4-methoxycyclohexyl)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-((trans)-4-(3-oxomorpholino)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(1-(1-methyl-1H-tetrazol-5-yl)piperidin-4-yl)cyclobutanecarboxamide; Racemic (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(1-(thiazol-2-yl)piperidin-4-yl)cyclobutanecarboxamide; (trans)-N-(1-(4-Cyanopyridin-2-yl)piperidin-4-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-N-(1-(3-Chloro-4-methoxybenzyl)piperidin-4-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(1-(pyridin-2-yl)piperidin-4-yl)cyclobutanecarboxamide; 2-((trans)-3-(5-Fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)-N,N-dimethyloxazole-4-carboxamide; (trans)-N-(6-Cyanopyridin-2-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; Racemic (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(6-(2-hydroxypropan-2-yl)spiro[3.3]heptan-2-yl)cyclobutanecarboxamide; Racemic (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-((trans)-4-((1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)cyclobutanecarboxamide; (trans)-N-((trans)-3-(5-Fluoro-2-methoxyphenoxy)cyclobutyl)-4-(2-hydroxypropan-2-yl)cyclohexanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-N-(5-Acetylthiazol-2-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(5-(2-hydroxypropan-2-yl)thiazol-2-yl)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(5-methyl-1,3,4-thiadiazol-2-yl)cyclobutanecarboxamide; (trans)-N-(4-Cyclopropylthiazol-2-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-((trans)-4-(2-hydroxy-2-methylpropoxy)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-N-(6-(2-Hydroxypropan-2-yl)spiro[3.3]heptan-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; Ethyl 2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)oxazole-4-carboxylate; N,N-Dimethyl-2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)oxazole-4-carboxamide; Racemic (trans)-3-(Quinolin-8-yloxy)-N-((trans)-4-((1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)cyclobutanecarboxamide; (trans)-N-(5-Acetyloxazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4,5-Dimethyloxazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; Ethyl 5-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)-4H-1,2,4-triazole-3-carboxylate; (trans)-N-(5-Methyloxazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-Cyclopropyloxazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(5-(tert-Butyl)-1,3,4-oxadiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; Racemic (trans)-N-((trans)-4-((1,1-Difluoropropan-2-yl)amino)cyclohexyl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(6-Methylpyridin-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-((trans)-4-Hydroxy-4-methylcyclohexyl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(Pyridin-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; trans-3-(8-Quinolinyloxy)-N-1,3-thiazol-2-ylcyclobutanecarboxamide; N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(quinolin-8-yloxy)azetidine-1-carboxamide; trans-N-(4-Acetylthiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; Racemic (trans)-3-(Quinolin-8-yloxy)-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)cyclobutanecarboxamide; (trans)-N-(4-Cyanothiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide, trifluoroacetic acid salt; 2-((trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxamide, trifluoroacetic acid salt; (trans)-N-(5-Cyan othiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; 2-((trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-5-carboxamide; Ethyl 2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxylate; 2-((trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxylic acid; (trans)-N-(4-(Cyclopropanecarbonyl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; Racemic (trans)-N-((trans)-6-(2-Hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; N-Methyl-2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxamide, trifluoroacetic acid salt; N,N-Dimethyl-2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxamide, trifluoroacetic acid salt; (trans)-N-(5-lsopropyl-1,3,4-thiadiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-(2-Hydroxypropan-2-yl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-3-(Quinolin-8-yloxy)-N-(4-(trifluoromethyl)thiazol-2-yl)cyclobutanecarboxamide; (trans)-N-(5-Acetylthiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(5-Methyl-1,3,4-thiadiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(5-(2-Hydroxypropan-2-yl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(5-(Prop-1-en-2-yl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-lsopropylthiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-Cyclopropylthiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(Oxazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-(2-Hydroxy-2-methylpropyl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide, trifluoroacetic acid salt; (trans)-N-(5-(Hydroxymethyl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-(tert-Butyl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; Racemic (trans)-N-(2,3-Dihydro-1H-inden-1-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(5-(2-Hydroxy-2-methylpropyl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(3-Cyclopropyl-1H-pyrazol-5-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-(Hydroxymethyl)thiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-3-(Quinolin-8-yloxy)-N-(1,3,4-thiadiazol-2-yl)cyclobutanecarboxamide; (trans)-N-(5-Methylthiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(4-Methylthiazol-2-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-(1-(Methylsulfonyl)piperidin-4-yl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-N-((trans)-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-3-(Quinolin-8-ylamino)-N-(thiazol-2-yl)cyclobutanecarboxamide; (trans)-N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(quinolin-8-ylamino)cyclobutanecarboxamide; (trans)-N-((trans)-3-(2-Hydroxypropan-2-yl)cyclobutyl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; (trans)-3-(Quinolin-8-yloxy)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)cyclobutanecarboxamide; N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(quinolin-8-yloxy)cyclobutanecarboxamide; N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(thieno[3,2-b]pyridin-3-yloxy)azetidine-1-carboxamide; (trans)-3-((5-Fluorobenzofuran-7-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(3-Bromophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(2,5-Difluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(2-Chloro-5-fluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-methylpyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(5-methylpyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(6-propionylspiro[3.3]heptan-2-yl)cyclobutanecarboxamide; N-(2-Ethoxyethyl)-6-(3-((trans)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)cyclobutanecarboxamido)azetidin-1-yl)pyridazine-3-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(pyrazin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic 3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-methylazetidine-1-carboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(3-methyl-1-(pyridazin-3-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(3-methyl-1-(pyrimidin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-methylpyridin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-methylazetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-methylpyridazin-3-yl)azetidin-3-yl)cyclobutanecarboxamide, trifluoroacetic acid salt; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(4-(methylsulfonyl)phenyl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(4-morpholinophenyl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-(5-methylpyridin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyridazin-3-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-(pyrazin-2-yl)azetidin-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl)phenyl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(3-morpholinophenyl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-methyl-1H-pyrazol-5-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(thiophen-2-ylmethyl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(3-methyl-1-(pyrimidin-2-yl)azetidin-3-yl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(thiophen-3-ylmethyl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-cyclohexylcyclobutanecarboxamide; Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1,1-dioxidotetrahydrothiophen-3-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-((5-methylfuran-2-yl)methyl)cyclobutanecarboxamide; Racemic 3-(Fluoro(quinolin-8-yl)methyl)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carboxamide; (trans)-3-(2;5-Dichlorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; N-((trans-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(2-(trifluoromethoxy)phenoxy)azetidine-1-carboxamide; (trans)-N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(2-(trifluoromethoxy)phenoxy)cyclobutanecarboxamide; 3-(Benzofuran-7-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carboxamide; (trans)-3-(Benzofuran-7-yloxy)-N-(5-cyanothiazol-2-yl)cyclobutanecarboxamide; Ethyl 2-(2-((trans)-3-(benzofuran-7-yloxy)cyclobutanecarboxamido)thiazol-4-yl)acetate; Ethyl 2-(5-((trans)-3-(benzofuran-7-yloxy)cyclobutanecarboxamido)-1,3,4-thiadiazol-2-yl)acetate; (trans)-N-(5-Acetylthiazol-2-yl)-3-(benzofuran-7-yloxy)cyclobutanecarboxamide; (trans)-3-(Benzofuran-7-yloxy)-N-(5-(2-hydroxypropan-2-yl)thiazol-2-yl)cyclobutanecarboxamide; (trans)-3-(Benzofuran-7-yloxy)-N-(5-methyl-1,3,4-thiadiazol-2-yl)cyclobutanecarboxamide; (trans)-3-(Benzofuran-7-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-((2;3-Dihydrobenzofuran-7-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-((3-Bromobenzofuran-7-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-((3-methylbenzofuran-7-yl)oxy)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-((3-bromobenzofuran-7-yl)oxy)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(5-chloro-2-(difluoromethoxy)phenoxy)cyclobutanecarboxamide; (trans)-3-(5-Chloro-2-(difluoromethoxy)phenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(5-chloro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(5-Chloro-2-methoxyphenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(4-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(4-Fluoro-2-meth oxyphe noxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(2-(Difluoromethoxy)phenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-(4-Acetylthiazol-2-yl)-3-(4-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-((3-Fluoroquinolin-8-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-((3-Fluoroquinolin-8-yl)oxy)-N-(thiazol-2-yl)cyclobutanecarboxamide; (trans)-3-(2-Chlorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(3,5-Difluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-3-(2-methoxyphenoxy)cyclobutanecarboxamide; (trans)-3-(3-Ethylphenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; Racemic (trans)-3-(3-Chlorophenoxy)-N-(2,3-dihydro-1H-inden-1-yl)cyclobutanecarboxamide; (trans)-3-(3-Chlorophenoxy)-N-(thiazol-2-yl)cyclobutanecarboxamide; (trans)-3-(3-Chlorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(3-Fluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-(3-Chloro-5-fluorophenoxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-((5-Fluoroquinolin-8-yl)oxy)-N-(thiazol-2-yl)cyclobutanecarboxamide, trifluoroacetic acid salt; (trans)-3-((5-Fluoroquinolin-8-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-3-((6-Fluoroquinolin-8-yl)oxy)-N-((trans)-3-(2-hydroxypropan-2-yl)cyclobutyl)cyclobutanecarboxamide; (trans)-3-((6-Fluoroquinolin-8-yl)oxy)-N-(thiazol-2-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluoroquinolin-8-yl)oxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)cyclobutanecarboxamide; (trans)-N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(quinazolin-8-yloxy)cyclobutanecarboxamide; (trans)-3-((1H-Benzo[d]imidazol-4-yl)oxy)-N-(thiazol-2-yl)cyclobutanecarboxamide, di-trifluoroacetic acid salt; (trans)-N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-(imidazo[1,2-a]pyridin-8-yloxy)cyclobutanecarboxamide; 3-(Benzo[d]isothiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-1-carboxamide; N-((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)-3-((2-methylbenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1H-pyrazol-5-yl)cyclobutanecarboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(3-cyclopropyl-1H-pyrazol-5-yl)cyclobutanecarboxamide; (trans)-3-((6-Fluorobenzo[d]thiazol-4-yl)oxy)-N-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)cyclobutanecarboxamide; (2S,3S)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-methylazetidine-1-carboxamide; (2R,3R)-3-(Benzo[d]thiazol-4-yloxy)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-methylazetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(4-(methylsulfonyl)phenyl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(6-methylpyrimidin-4-yl)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl)phenyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(3-morpholinophenyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(4-morpholinophenyl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-(methylsulfonyl)pyridin-2-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(2-cyclopropylpyrimidin-4-yl)azetidine-1-carboxamide; N-(2-Cyclopropylpyrimidin-4-yl)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(3-(pyrimidin-2-ylamino)bicyclo[1.1.1]pentan-1-yl)cyclobutane-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(3-(2-hydroxpropan-2-yl)bicyclo[1.1.1]pentan-1-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(4-(2-hydroxypropan-2-yl)cuban-1-yl)azetidine-1-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(3-(2-hydroxpropan-2-yl)bicyclo[1.1.1]pentan-1-yl)cyclobutane-1-carboxamide; Ethyl (3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutane-1-carboxamido)bicyclo[1.1.1]pentan-1-yl)carbamate; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(4-(2-hydroxpropan-2-yl)cuban-1-yl)cyclobutane-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-methyl-1,3,4-thiadiazol-2-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-methoxpyridin-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-methyl-1H-pyrazol-4-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(1-ethyl-1H-tetrazol-5-yl)azetidine-1-carboxamide; Methyl 4-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutane-1-carboxamido)bicyclo[2.2.2]octane-1-carboxylate; Methyl 4-(3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)bicyclo[2.2.2]octane-1-carboxylate; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-isopropyl-1,3,4-oxadiazol-2-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(4-cyano-3-methyl-1H-pyrazol-5-yl)azetidine-1-carboxamide; 4-((1-(((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)carbamoyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxamide; (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(5-methyl-1,3,4-thiadiazol-2-yl)cyclobutane-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-isopropyl-1,3,4-thiadiazol-2-yl)azetidine-1-carboxamide; (trans)-N-(5-(Ethoxymethyl)-1H-1,2,4-triazol-3-yl)-3-((6-fluorobenzo[d]thiazol-4-yl)oxy)cyclobutanecarboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(5-methyl-1,2,4-thiadiazol-3-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(3-isopropyl-1,2,4-thiadiazol-5-yl)azetidine-1-carboxamide; 3-(Benzo[d]thiazol-4-yloxy)-N-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)azetidine-1-carboxamide; and 3-(Benzo[d]thiazol-4-yloxy)-N-(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)azetidine-1-carboxamide; and pharmaceutically acceptable salts thereof.

The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formula (I).

The salts, including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N′-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-1′-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

The compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form.

The compounds of Formula (I) or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Accordingly, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may exist in solvated and unsolvated forms.

The skilled artisan will further appreciate that certain compounds of Formula (I) or salts, including pharmaceutically acceptable salts thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. Accordingly, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may exist in a single crystalline form or in different polymorphic forms.

As used herein, when referring to Formula (I) it will be appreciated that any one of Formulas (II) through (IV) are also referenced unless the context dictates otherwise.

It will be appreciated that the following definitions apply to each of the aforementioned formulae and to all instances of these terms, unless the context dictates otherwise.

“Alkyl” refers to a hydrocarbon chain having the specified number of “carbon atoms”. For example, C 1 -C 6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms. Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes but is not limited to: methyl, ethyl, ethylene, ethynyl, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.

“Alkoxy” refers to an —O-alkyl group wherein “alkyl” is as defined herein. For example, C 1 -C 4 alkoxy refers to an alkoxy group having from 1 to 4 carbon atoms. Representative branched alkoxy groups have one, two, or three branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy.

“Aryl” refers to an aromatic hydrocarbon ring system. Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as but no limited to: phenyl, dihydroindene, naphthalene, tetrahydronaphthalene and biphenyl. Suitably aryl is phenyl.

“Cycloalkyl”, unless otherwise defined, refers to a saturated or unsaturated non aromatic hydrocarbon ring system having from three to eight carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring systems. For example, C 3 -C 8 cycloalkyl refers to a cycloalkyl group having from 3 to 8 member atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptyl and spiro heptane. Suitably Cycloalkyl includes: bicyclo[1.1.1]pentyl, cubanyl, bicyclo 2.2 2 octanyl, cyclohexyl, spiro heptanyl, cyclobutanyl, and cyclopropyl. Suitably Cycloalkyl includes: cyclohexyl, spiro heptanyl, cyclobutanyl, and cyclopropyl.

Suitably “Cycloalkyl”, refers to a saturated or unsaturated non aromatic hydrocarbon ring system having from three to seven carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring systems. For example, C 3 -C 7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptyl and spiro heptanyl.

“Halogen” refers to the halogen radicals fluoro, chloro, bromo, and iodo.

“Heteroaryl” refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl includes: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrahydroquinolinyl. Suitably, “heteroaryl” includes: pyrazolyl, thiazolyl, and tetrahydroquinolinyl.

“Bicycloheteroaryl” refers to two fused rings, at least one of which is aromatic, containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. Bicycloheteroaryl rings have from 6 to 11 member atoms. Bicycloheteroaryl includes: 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3-d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzoxadiazolyl, imidazothiazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridine, imidazo[4.5-b]pyridine, furopyridinyl and napthyridinyl.

“Heterocycle” and “Heterocycloalkyl” refers to a saturated or unsaturated non-aromatic monocyclic ring system containing 4 to 8 member atoms, of which 1 to 7 are carbon atoms and from 1 to 4 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycle and heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, and azetidinyl. Suitably, “Heterocycle” and “Heterocycloalkyl” includes: pyrrolidinyl, tetrahydropyranyl, oxazolidinyl, piperidinyl, and azetidinyl.

“Heteroatom” refers to a nitrogen, sulfur or oxygen atom.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry . Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

Ac (acetyl); Ac 2 O (acetic anhydride); ACN (acetonitrile); AIBN (azobis(isobutyronitrile)); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); BMS (borane—dimethyl sulphide complex); Bn (benzyl); Boc (tert-Butoxycarbonyl); Boc 2 O (di-tert-butyl dicarbonate); BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); CAN (cerric ammonium nitrate); Cbz (benzyloxycarbonyl); CSI (chlorosulfonyl isocyanate); CsF (cesium fluoride); DABCO (1,4-Diazabicyclo[2.2.2]octane); DAST (Diethylamino)sulfur trifluoride); DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene); DCC (Dicyclohexyl Carbodiimide); DCE (1,2-dichloroethane); DCM (dichloromethane); DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone); ATP (adenosine triphosphate); Bis-pinacolatodiboron (4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane); BSA (bovine serum albumin); C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase); CH 3 CN (acetonitrile); Cy (cyclohexyl); DCM (dichloromethane); DIEA (Hunig's base, N,N-Diisopropylethylamine, N-ethyl-N-(1-methylethyl)-2-propanamine); Dioxane (1,4-dioxane); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMEDA (N,N′-dimethylethylenediamine); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); DPPA (diphenyl phosphoryl azide); EDC (N-(3-dimethylaminopropyl)-N′ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); EtOAc (ethyl acetate); EtOH (ethanol); Et 2 O (diethyl ether); HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole); HOBt (1-hydroxybenzotriazole); HOAc (acetic acid); HPLC (high pressure liquid chromatography); HMDS (hexamethyldisilazide); IPA (isopropyl alcohol); Indoline (2,3-dihydro-1H-indole); KHMDS (potassium hexamethyldisilazide); LAH (lithium aluminum hydride); LDA (lithium diisopropylamide); LHMDS (lithium hexamethyldisilazide) MeOH (methanol); MTBE (methyl tert-butyl ether); mCPBA (m-chloroperoxybenzoic acid); NaHMDS (sodium hexamethyldisilazide); NBS (N-bromosuccinimide); PE (petroleum ether); Pd 2 (dba) 3 (Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl 2 ·DCM Complex([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex); PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate); RP-HPLC (reverse phase high pressure liquid chromatography); RT (room temperature); Sat. (saturated) SFC (supercritical fluid chromatography); SGC (silica gel chromatography); SM (starting material); TLC (thin layer chromatography); TEA (triethylamine); TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl, free radical); TFA (trifluoroacetic acid); and THF (tetrahydrofuran).

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCl.

The compounds according to Formula (I) are prepared using conventional organic synthetic methods. A suitable synthetic route is depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

As used in the Schemes, “r” groups represent corresponding positional groups on any of Formulas I to IV.

In one method of preparation, the cyclobutane carboxamides may be prepared from phenols shown in Scheme 1. First, coupling of suitable phenols with appropriate (cis)-methyl 3-hydroxycyclobutanecarboxylates via Mitsunobu conditions or direct alkylation with (trans)-methyl 3-((methylsulfonyl)oxy)cyclobutanecarboxylates provides the substituted cyclobutane carboxylic esters. Subsequent ester hydrolysis and coupling of the resulting acids with suitable amines yield the desired cyclobutane carboxamides.

In another method of preparation, the cyclobutane carboxamides may be prepared from anilines as shown in Scheme 2. Sulfonylation of suitable anilines with p-toluenesulfonyl chloride followed by coupling of the sulfonamide with appropriate (cis)-methyl 3-hydroxycyclobutanecarboxylates via Mitsunobu conditions provides the substituted cyclobutane carboxylic esters. Subsequent ester hydrolysis followed by acidic cleavage of the sulfonyl group provides the substituted cyclobutane carboxylic acids. Coupling of the carboxylic acids with suitable amines yield the desired cyclobutane carboxamides.

In another method of preparation, the azetidine ureas may be prepared from phenols as shown in Scheme 3. Alkylation of suitable phenols with appropriate tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylates followed by acidic removal of the N-Boc protecting group provides the substituted azetidines. Coupling of the azetidine with p-nitrophenylcarbamates derived from suitable amines yield the desired azetidine ureas. Alternatively, coupling of the azetidine with suitable amines and triphosgene yield the desired azetidine ureas.

In an alternative method of preparation, the azetidine ureas may be derived from the substituted azetidine intermediate depicted in Scheme 3 as shown in Scheme 4. Acylation of a suitable azetidine with 4-nitrophenyl chloroformate provides the azetidine carbamates which upon heating with suitable amines yields the desired azetidine ureas.

In an alternative method of preparation, the azetidine ureas may be derived as shown in Scheme 5. Aromatic substitution of an aromatic ring containing a suitable leaving group with the alkoxides of appropriate tert-butyl 3-hydroxyazetidine-1-carboxylates followed by acidic removal of the N-Boc protecting group provides the substituted azetidines depicted in Scheme 3 and Scheme 4. Further elaboration to the desired azetidine ureas can be achieved using the methods described in Scheme 3 and Scheme 4.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.

The inventors have shown that inhibitors of Hematopoietic Prostaglandin D Synthase (HPGDS) reduce muscle damage and preserve muscle function when administered prior to muscle damage in an in vivo assay for muscle function. Furthermore, the inventors have shown that when an HPGDS inhibitor is administered after muscle damage in the same assay, recovery of muscle function is enhanced. These results support a role for the use of HPGDS inhibitors in the treatment of muscle degenerative disorders and muscle injury.

In one aspect, the invention provides a method of treating a muscle degenerative disorder comprising administering to a human an HPGDS inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof.

In particular embodiments, the muscle degenerative disorder is muscular dystrophy, myotonic dystrophy, polymyositis, or dermatomyositis.

For example, the compounds of Formula (I) or a pharmaceutically acceptable salt thereof may be used to treat a muscular dystrophy disorder selected from Duchenne MD, Becker MD, Congenital MD (Fukuyama), Emery Dreifuss MD, Limb girdle MD, and Fascioscapulohumeral MD.

The the compounds of Formula (I) or a pharmaceutically acceptable salt thereof may also be used to treat myotonic dystrophy type I (DM1 or Steinert's), myotonic dystrophy type II (DM2 or proximal myotonic myopathy), or congenital myotonia.

In some embodiments, the muscle injury is a surgery-related muscle injury, a traumatic muscle injury, a work-related skeletal muscle injury, or an overtraining-related muscle injury.

Non-limiting examples of surgery-related muscle injuries include muscle damage due to knee replacement, anterior cruciate ligament (ACL) repair, plastic surgery, hip replacement surgery, joint replacement surgery, tendon repair surgery, surgical repair of rotator cuff disease and injury, and amputation.

In one embodiment, the muscle injury is a surgery-related muscle injury and the treatment method provides for administration of at least one dose of an HPGDS inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof prior to the surgery (for example, within one day before the surgery) followed by periodic administration of a dose of the HPGDS inhibitor during the recovery period.

In another embodiment, the muscle injury is a surgery-related muscle injury and the treatment method provides for administration of at least one high dose of an HPGDS inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof within one day to one week following the surgery.

In yet another embodiment, the muscle injury is a surgery-related muscle injury and the treatment method provides for administration of at least one high dose of an HPGDS inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof within one day to one week following the surgery, followed by periodic administration of a dose of the HPGDS inhibitor during the recovery period.

Non-limiting examples of traumatic muscle injuries include battlefield muscle injuries, auto accident-related muscle injuries, and sports-related muscle injuries. Traumatic injury to the muscle can include lacerations, blunt force contusions, shrapnel wounds, muscle pulls or tears, burns, acute strains, chronic strains, weight or force stress injuries, repetitive stress injuries, avulsion muscle injury, and compartment syndrome.

In one embodiment, the muscle injury is a traumatic muscle injury and the treatment method provides for administration of at least one dose of an HPGDS inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof, immediately after the traumatic injury (for example, within one day of the injury) followed by periodic administration of a dose of the HPGDS inhibitor during the recovery period.

Non-limiting examples of work-related muscle injuries include injuries caused by highly repetitive motions, forceful motions, awkward postures, prolonged and forceful mechanical coupling between the body and an object, and vibration.

Overtraining-related muscle injuries include unrepaired or under-repaired muscle damage coincident with a lack of recovery or lack of an increase of physical work capacity.

In an additional embodiment, the muscle injury is exercise or sports-induced muscle damage resulting including exercise-induced delayed onset muscle soreness (DOMS).

In some embodiments, the invention encompasses a therapeutic combination in which the HPGDS inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof is administered in a subject in combination with the implantation of a biologic scaffold (e.g. a scaffold comprising extracellular matrix) that promotes muscle regeneration. Such scaffolds are known in the art. See, for example, Turner and Badylack (2012) Cell Tissue Res. 347(3):759-74 and U.S. Pat. No. 6,576,265. Scaffolds comprising non-crosslinked extracellular matrix material are preferred.

In another aspect, the invention provides a method of treating tendon damage where the method comprises administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. In a particular embodiment, the invention includes a method of enhancing the formation of a stable tendon-bone interface. In a related embodiment, the invention provides a method of increasing the stress to failure of tendons, for example surgically-repaired tendons. In an additional embodiment, the invention provides a method of reducing fibrosis at the repair site for surgically-repaired tendons. In a particular embodiment, the invention provides a method of treating tendon damage associated with rotator cuff injury, or tendon damage associated with surgical repair of rotator cuff injury.

In another aspect, the invention provides a method of treating a disease state selected from: allergic diseases and other inflammatory conditions such as asthma, aspirin-exacerbated respiratory disease (AERD), cough, chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), bronchoconstriction, allergic rhinitis (seasonal or perennial), vasomotor rhinitis, rhinoconjuctivitis, allergic conjunctivitis, food allergy, hypersensitivity lung diseases, eosinophilic syndromes including eosinophilic asthma, eosinophilic pneumonitis, eosinophilic oesophagitis, eosinophilic granuloma, delayed-type hypersensitivity disorders, atherosclerosis, rheumatoid arthritis, pancreatitis, gastritis, inflammatory bowel disease, osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratory distress syndrome, bronchiolitis, sinusitis, cystic fibrosis, actinic keratosis, skin dysplasia, chronic urticaria, eczema and all types of dermatitis including atopic dermatitis or contact dermatitis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

By the term “treating” and derivatives thereof as used herein, in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The skilled artisan will appreciate that “prevention” is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, the term “effective amount” and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

The subject to be treated in the methods of the invention is typically a mammal in need of such treatment, preferably a human in need of such treatment.

The pharmaceutically active compounds within the scope of this invention are useful as inhibitors of HPGDS in mammals, particularly humans, in need thereof.

The present invention therefore provides a method of treating neurodegenerative diseases, musculoskeletal diseases and other conditions requiring HPGDS inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as HPGDS inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular and parenteral. Suitably, a HPGDS inhibitor may be delivered directly to the brain by intrathecal or intraventricular route, or implanted at an appropriate anatomical location within a device or pump that continuously releases the HPGDS inhibitor drug.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001-500 mg/kg of active compound, preferably 0.001-100 mg/kg. When treating a human patient in need of a HPGDS inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular HPGDS inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

When administered to prevent organ damage in the transportation of organs for transplantation, a compound of Formula (I) is added to the solution housing the organ during transportation, suitably in a buffered solution.

The method of this invention of inducing HPGDS inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective HPGDS inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a HPGDS inhibitor.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating musculoskeletal diseases such as Duchenne Muscular Dystrophy, spinal cord contusion injury, neuroinflammatory diseases such as Multiple Sclerosis or neurodegenerative diseases such as Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

The invention also provides for a pharmaceutical composition for use as a HPGDS inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a HPGDS inhibitor.

By the term “co-administration” as used herein is meant either simultaneous administration or any manner of separate sequential administration of a HPGDS inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of conditions in which a H-PGDS inhibitor is indicated. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of H-PGDS inhibition. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of neurodegenerative diseases, musculoskeletal diseases and diseases associated with H-PGDS inhibition.

The invention also provides a pharmaceutical composition comprising from 0.5 to 1,000 mg of a compound of Formula (I) or pharmaceutically acceptable salt thereof and from 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Mass Directed Auto-Preparative HPLC (MDAP)

Mass Directed Auto-Preparative HPLC is undertaken under the conditions given below. Detection is by absorption over the wavelength range 210 nm to 350 nm and mass spectra are recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.

Method A

Method A is conducted on a Waters SunFire C18 column (typically 150 mm×30 mm i.d. with 5 micron particle size) at ambient temperature. The solvents employed are:

A=0.1% v/v solution of formic acid in water

B=0.1% v/v solution of formic acid in acetonitrile.

Method B

Method B is conducted on a Waters XBridge C18 column (typically 100 mm×30 mm i.d. with 5 micron particle size) at ambient temperature. The solvents employed are:

A=10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia solution.

B=acetonitrile.

Method C

Method C is conducted on a Waters SunFire C18 column (typically 150 mm×30 mm i.d. with 5 micron particle size) at ambient temperature. The solvents employed are:

A=0.1% v/v solution of trifluoroacetic acid in water

B=0.1% v/v solution of trifluoroacetic acid in acetonitrile.

The following Examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Intermediate 1: tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

To a stirred, cooled (0° C.) solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol in DCM (5 mL) was added triethylamine (0.90 mL, 6.46 mmol) followed by methanesulfonyl chloride (0.25 mL, 3.21 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated brine and extracted twice with EtOAc. The combined organic layers were dried over Na 2 SO 4 and filtered. Solvent was removed under reduced pressure. The remaining material was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient. The appropriate fractions (identified by TLC, silica gel, 50% EtOAc/hexanes, KMnO 4 stain) were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (699 mg, 96%) as a colorless oil that slowly solidified. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.39 (s, 9H), 3.25 (s, 3H), 3.88-3.94 (m, 2H), 4.19-4.36 (m, 2H), 5.22-5.28 (m, 1H); LC-MS (LC-ES) M+H-tert-Bu=196.

Intermediate 2: 3-(2-(Difluoromethoxy)-5-fluorophenoxy)azetidine hydrochloride

A. 2-(Benzyloxy)-4-fluorobenzaldehyde

To a stirred solution of 4-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol) in DMF (50 mL) was added potassium carbonate (5.92 g, 42.8 mmol) and benzyl bromide (4.79 mL, 42.8 mmol). After 3 h, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The organic layers were dried over Na 2 SO 4 , evaporated and dried under vacuum. The residue was purified on silica gel eluting with a 0%-40% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (7.3 g, 89%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.28 (s, 2H), 6.78-7.01 (m, 1H), 7.23-7.26 (m, 1H), 7.29-7.39 (m, 3H), 7.45-7.54 (m, 2H), 7.69-7.75 (m, 1H), 10.29 (s, 1H); LC-MS (LC-ES) M+H=231.

B. 2-(Benzyloxy)-4-fluorophenol

3-Chlorobenzoperoxoic acid (14.0 g, 81.0 mmol) was added to a solution of 2-(benzyloxy)-4-fluorobenzaldehyde (Intermediate 2A) (7.50 g, 32.6 mmol) in DCM (100 mL) and stirred at 40° C. overnight, cooled and washed with saturated NaHCO 3 (3×) and brine. The organic layer was dried over Na 2 SO 4 and evaporated. The residue was dissolved in THF (100 mL) and water (50 mL), and lithium hydroxide (2.34 g, 98.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Citric acid was added until pH neutral, and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified on silica gel eluting with a 0%-40% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (5.5 g, 78%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.11 (s, 2H), 6.53-6.59 (m, 1H), 6.74-6.78 (m, 1H), 6.87-6.91 (m, 1H), 7.31-7.36 (m, 1H), 7.39-7.42 (m, 2H), 7.45-7.49 (m, 2H), 8.95 (s, 1H); LC-MS (LC-ES) M−H=217.

C. 2-(Benzyloxy)-1-(difluoromethoxy)-4-fluorobenzene

To a stirred, cooled (−78° C.) solution of 2-(benzyloxy)-4-fluorophenol (Intermediate 2B) (175 mg, 0.802 mmol) and potassium hydroxide (900 mg, 16.0 mmol) in acetonitrile (5 mL) and water (5 mL) was added diethyl (bromodifluoromethyl)phosphonate (0.30 mL, 1.69 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring for the weekend, the mixture was extracted twice with Et 2 O. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with a 0%-25% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and dried in vacuo to give the title compound (92 mg, 43%) as a colorless oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.19 (s, 2H), 6.78-6.84 (m, 1H), 7.18-7.27 (m, 2H), 7.22 (s, 1H), 7.33-7.38 (m, 1H), 7.39-7.44 (m, 2H), 7.45-7.48 (m, 2H); LC-MS (LC-ES) peak at T=0.95 min.

D. 2-(Difluoromethoxy)-5-fluorophenol

To a stirred solution of 2-(benzyloxy)-1-(difluoromethoxy)-4-fluorobenzene (Intermediate 2C) (90 mg, 0.336 mmol) in methanol (3 mL) under a nitrogen atmosphere was added 10% Pd/C (9 mg, 0.085 mmol). The reaction vessel was evacuated under reduced pressure and purged with hydrogen three times. The mixture was placed under a nitrogen atmosphere, fitted with a hydrogen filled balloon and stirred overnight under a hydrogen atmosphere. The mixture was filtered through a pad of Celite®, washing with DCM and EtOH. The filtrate was evaporated to dryness to give the crude title compound (30 mg, 50%), which was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 6.59-6.65 (m, 1H), 6.75 (dd, J=10, 4 Hz, 1H), 6.97 (s, 1H), 7.13 (dd, J=8, 4 Hz, 1H); LC-MS (LC-ES)

E. tert-Butyl 3-(2-(difluoromethoxy)-5-fluorophenoxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (40 mg, 0.16 mmol) and 2-(difluoromethoxy)-5-fluorophenol (Intermediate 2D) (26 mg, 0.15 mmol) in DMF (2 mL) was added cesium carbonate (55 mg, 0.17 mmol). The mixture was heated to 80° C. overnight, and LC/MS showed starting material remained. Heating was continued overnight, and the mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 0%-25% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (27 mg, 55%) as a colorless oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.36 (s, 9H), 3.76-3.82 (m, 2H), 4.26-4.32 (m, 2H), 4.99-5.05 (m, 1H), 6.79-6.87 (m, 2H), 7.04 (s, 1H), 7.21-7.26 (m, 1H); LC-MS (LC-ES) M+H-Boc=234.

F. 3-(2-(Difluoromethoxy)-5-fluorophenoxy)azetidine hydrochloride

4 N Hydrochloric acid (1 mL, 4.00 mmol) in dioxane was added to tert-butyl 3-(2-(difluoromethoxy)-5-fluorophenoxy)azetidine-1-carboxylate (Intermediate 2E) (26 mg, 0.078 mmol). The mixture was stirred for 4 h and then concentrated under reduced pressure. The remaining material was diluted with DCM and concentrated under reduced pressure. This process was repeated twice to give the title compound (21 mg). LC-MS (LC-ES) peak at T=0.38 min; M+H=234.

Intermediate 3: 4-Nitrophenyl ((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)carbamate

To a stirred, cooled (0° C.) solution of 4-nitrophenyl chloroformate (230 mg, 1.14 mmol) in DCM (4 mL) was added 2-((trans)-4-aminocyclohexyl)propan-2-ol (150 mg, 0.954 mmol) followed by N,N-diisopropylethylamine (0.20 mL, 1.2 mmol). The mixture was warmed to room temperature, stirred overnight and concentrated. The remaining material was purified on silica gel eluting with a 0%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (97 mg, 31%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.01 (s, 6H), 1.03-1.27 (m, 5H), 1.87 (dd, J=48, 16 Hz, 4H), 3.22-3.43 (m, 1H), 4.04 (s, 1H), 7.39 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 1H), 8.25 (d, J=8 Hz, 2H); LC-MS (LC-ES) M+H=323.

Intermediate 4: (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylate

Triphenylphosphine-PS (3.27 g, 12.5 mmol) was added to a solution of 2-(difluoromethoxy)-5-fluorophenol (Intermediate 2D) (1.85 g, 10.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (1.33 mL, 12.5 mmol) was added, followed by DIAD (2.4 mL, 13 mmol). The reaction mixture was then warmed to room temperature, stirred for 12 h, filtered, and concentrated. The remaining material was purified on silica gel eluting with a 0%-70% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (1.79 g, 58%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.27-2.45 (m, 2H), 2.57-2.79 (m, 2H), 3.13-3.27 (m, 1H), 3.32 (s, 3H), 4.90 (dd, J=7, 6 Hz, 1H), 6.66-6.95 (m, 2H), 7.03 (s, 1H), 7.11-7.34 (m, 1H); LC-MS (LC-ES) peak at T=0.86 min.

B. (trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylate (Intermediate 4A) (1.75 g, 6.02 mmol) in THF (30 mL) was added a solution of LiOH (0.432 g, 18.1 mmol) in water (15 mL). The reaction mixture was stirred at room temperature for 1 h. Citric acid was added until pH=4 and the reaction was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated to give the title compound (1.74 g, quantitative yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.35 (ddd, J=13, 10, 6 Hz, 2H), 2.61-2.76 (m, 2H), 3.10 (dd, J=6, 5 Hz, 1H), 4.89 (dd, J=6, 5 Hz, 1H), 6.64-6.94 (m, 2H), 7.02 (s, 1H), 7.11-7.38 (m, 1H), 12.33 (br s, 1H); LC-MS (LC-ES) M−H=275.

Intermediate 5: 2-(3-Aminoazetidin-1-yl)thiazole-5-carbonitrile dihydrochloride, Methyl 2-(3-aminoazetidin-1-yl)thiazole-5-carbimidate dihydrochloride, and 2-(3-Aminoazetidin-1-yl)thiazole-5-carboxamide dihydrochloride

A. tert-Butyl (1-(5-cyanothiazol-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate hydrochloride (300 mg, 1.44 mmol) in acetonitrile (10 mL), 2-chlorothiazole-5-carbonitrile (208 mg, 1.44 mmol) was added, followed by N,N-diisopropylethylamine (0.75 mL, 4.3 mmol). The mixture was heated in a microwave at 110° C. for 5 h, then allowed to sit at room temperature for two days as crystals appeared. This solid product was collected by filtration, the filtrate was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure, combined with the previously harvested crystal solid and placed in vacuo to give the title compound as a white solid (90 mg, 22%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.45 (s, 9H), 4.03-4.07 (m, 2H), 4.41-4.49 (m, 2H), 4.71 (br s, 1H), 5.05 (br s, 1H), 7.67 (s, 1H); LC-MS (LC-ES) M+H-Boc=181.

B. 2-(3-Aminoazetidin-1-yl)thiazole-5-carbonitrile dihydrochloride, Methyl 2-(3-aminoazetidin-1-yl)thiazole-5-carbimidate dihydrochloride, and 2-(3-Aminoazetidin-1-yl)thiazole-5-carboxamide dihydrochloride

To tert-butyl (1-(5-cyanothiazol-2-yl)azetidin-3-yl)carbamate (Intermediate 5A) (370 mg, 1.32 mmol) in DCM (5 mL), HCl (10 mL, 40.0 mmol) (4 M in dioxane) was added. The mixture was stirred at room temperature for 1 h and the solvent was removed to give a mixture of the crude title compounds as a tan solid which was used without further purification.

2-(3-Aminoazetidin-1-yl)thiazole-5-carbonitrile dihydrochloride

LC-MS (LC-ES) peak at T=0.41 min; M+H=181.

Methyl 2-(3-aminoazetidin-1-yl)thiazole-5-carbimidate dihydrochloride

LC-MS (LC-ES) peak at T=0.40 min; M+H=213.

2-(3-Aminoazetidin-1-yl)thiazole-5-carboxamide dihydrochloride

LC-MS (LC-ES) peak at T=0.29 min; M+H=199.

Intermediate 6: 2-(3-Aminoazetidin-1-yl)pyrimidine-4-carboxamide dihydrochloride and 2-(3-Aminoazetidin-1-yl)pyrimidine-4-carbonitrile dihydrochloride

A. tert-Butyl (1-(4-cyanopyrimidin-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate hydrochloride (300 mg, 1.44 mmol) in acetonitrile (10 mL), 2-chloropyrimidine-4-carbonitrile (241 mg, 1.73 mmol) was added, followed by N,N-diisopropylethylamine (0.75 mL, 4.3 mmol). The mixture was heated in a microwave at 90° C. for 3 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (423 mg, quantitative yield). 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 3.91-3.99 (m, 2H), 4.40-4.48 (m, 2H), 4.63 (br s, 1H), 5.03 (br s, 1H), 6.81 (d, J=5 Hz, 1H), 8.45 (d, J=5 Hz, 1H); LC-MS (LC-ES) M+H-Boc=176.

B. 2-(3-Aminoazetidin-1-yl)pyrimidine-4-carboxamide dihydrochloride and 2-(3-Aminoazetidin-1-yl)pyrimidine-4-carbonitrile dihydrochloride

To tert-butyl (1-(4-cyanopyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 6A) (68 mg, 0.25 mmol) in DCM (5 mL), HCl (10 mL, 40 mmol) (4 M in dioxane) was added. The mixture was stirred at room temperature for 1 h and the solvent was removed to give a mixture of the title compounds as a tan solid which was used without further purification.

2-(3-Aminoazetidin-1-yl)pyrimidine-4-carboxamide dihydrochloride

LC-MS (LC-ES) M+H=194.

2-(3-Aminoazetidin-1-yl)pyrimidine-4-carbonitrile dihydrochloride

LC-MS (LC-ES) M+H=176.

Intermediate 7: 1-(2-Chloropyrimidin-4-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(2-chloropyrimidin-4-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.40 mmol) in methanol (10 mL), MP-carbonate (3.1 mmol/g) was added. The mixture was stirred for 1 h, filtered and washed with MeOH. To this mixture, 2,4-dichloropyrimidine (428 mg, 2.88 mmol) was added followed by N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The mixture was stirred at room temperature for 2 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (412 mg, 60%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.45 (s, 9H), 3.88-4.00 (m, 2H), 4.33-4.47 (m, 2H), 4.55-4.73 (m, 1H), 4.92-5.10 (m, 1H), 6.07 (d, J=6 Hz, 1H), 8.02 (d, J=6 Hz, 1H); LC-MS (LC-ES) M+H=285, 287 (CI pattern).

B. 1-(2-Chloropyrimidin-4-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(2-chloropyrimidin-4-yl)azetidin-3-yl)carbamate (Intermediate 7A) (410 mg, 1.44 mmol) in DCM (3 mL), HCl (6 mL, 24 mmol) (4 M in dioxane) was added. The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo to give the title compound as a white solid (374 mg, quantitative yield). 1 H NMR (400 MHz, CD 3 OD) δ 4.35-4.45 (m, 3H), 4.68-4.74 (m, 2H), 6.75 (d, J=7 Hz, 1H), 8.18 (d, J=7 Hz, 1H); LC-MS (LC-ES) M+H=185, 187 (CI pattern).

Intermediate 8: 1-(4-Chloropyrimidin-2-yl)azetidin-3-amine hydrochloride

A. tert-Butyl (1-(4-chloropyrimidin-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.40 mmol) in methanol (10 mL) was added MP-carbonate (3.1 mmol/g). The mixture was stirred for 1 h, filtered and washed with MeOH. To this mixture, 2,4-dichloropyrimidine (428 mg, 2.88 mmol) was added followed by N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The mixture was stirred at room temperature for 2 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (68 mg, 10%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 3.90-3.96 (m, 2H), 4.42-4.47 (m, 2H), 4.56-4.66 (m, 1H), 4.92-5.01 (m, 1H), 6.57 (d, J=5 Hz, 1H), 8.16 (d, J=5 Hz, 1H); LC-MS (LC-ES) M+H=285, 287 (CI pattern).

B. 1-(4-Chloropyrimidin-2-yl)azetidin-3-amine hydrochloride

To tert-butyl (1-(4-chloropyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 8A) (68 mg, 0.24 mmol) in DCM (1.5 mL) was added 4 M HCl in dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo to give the title compound as a white solid (60 mg, quantitative yield). 1 H NMR (400 MHz, CD 3 OD) δ 4.21-4.29 (m, 3H), 4.54-4.62 (m, 2H), 6.92 (d, J=6 Hz, 1H), 8.31 (d, J=6 Hz, 1H); LC-MS (LC-ES) M+H=185, 187 (CI pattern).

Intermediate 9: 1-(5-Fluoropyrimidin-2-yl)azetidin-3-amine dihydrobromide

A. Benzyl (1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)carbamate

To a microwave reaction vial with benzyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.0 mmol) in acetonitrile (8 mL) was added 2-chloro-5-fluoropyrimidine (546 mg, 4.1 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.2 mmol). The mixture was heated with a heating gun to form a solution and heated in a microwave at 155° C. for 5 h. The solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 0%-60% EtOAc/EtOH (3:1) in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (560 mg, 90%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.81-3.85 (m, 2H), 4.31-4.36 (m, 2H), 4.55-4.62 (m, 1H), 5.03 (s, 2H), 5.09-5.17 (m, 1H), 7.19-7.32 (m, 5H), 8.11 (s, 2H); LC-MS (LC-ES) M+H=303.

B. 1-(5-Fluoropyrimidin-2-yl)azetidin-3-amine dihydrobromide

To benzyl (1-(pyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 9A) (110 mg, 0.39 mmol) was added 33% HBr in AcOH (0.06 mL, 0.39 mmol). The mixture was stirred at room temperature for 1.5 h and the solvent was removed in vacuo to give the title compound as a tan solid (112 mg, 93%). 1 H NMR (400 MHz, CD 3 OD) δ 4.21-4.21 (m, 2H), 4.21-4.26 (m, 1H), 4.49-4.55 (m, 2H), 8.45 (s, 2H); LC-MS (LC-ES) M+H=169.

Alternatively 1-(5-Fluoropyrimidin-2-yl)azetidin-3-amine can be prepared as the dihydrochloride

Intermediate 9: 1-(5-Fluoropyrimidin-2-yl)azetidin-3-amine dihydrochloride

C. tert-Butyl (1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)carbamate

To a microwave reaction vial with tert-butyl azetidin-3-ylcarbamate hydrochloride (732 mg, 3.51 mmol) in acetonitrile (2 mL) was added 2-chloro-5-fluoropyrimidine (465 mg, 3.51 mmol) and N,N-diisopropylethylamine (1.23 mL, 7.02 mmol). The mixture was heated in a microwave (125° C.) for 2.5 h, cooled and some precipitated product collected by filtration. The filtrate was concentrated in vacuo and the residue purified on silica gel eluting with a 10%-50% EtOAc/EtOH (3:1) in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (620 mg, 65%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 3.89-3.98 (m, 2H), 4.32-4.39 (m, 2H), 4.43-4.53 (m, 1H), 8.31 (s, 2H); LC-MS (LC-ES) M+H=269.

D. 1-(5-Fluoropyrimidin-2-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 9C) (620 mg, 2.31 mmol) in MeOH (3 mL) (with a small portion of DCM to facilitate solubility) was added 4 N HCl in dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature for 3 h, and the solvent was removed in vacuo to give the title compound as a white solid (652 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.11-4.20 (m, 2H), 4.20-4.26 (m, 1H), 4.50 (dd, J=10, 7 Hz, 2H), 8.47 (s, 2H); LC-MS (LC-ES) M+H=169.

Intermediate 10: Racemic 2-(((trans)-4-Aminocyclohexyl)oxy)-1-cyclopropylethanol

A. trans-4-(Dibenzylamino)cyclohexanol

Benzyl bromide (60 g, 351 mmol) was added to (trans)-4-aminocyclohexanol hydrochloride (20 g, 174 mmol) and sodium bicarbonate (40 g, 476 mmol) in EtOH (400 mL) at room temperature. The reaction was then heated to reflux for 36 h, filtered and concentrated to give a solid. To this was added hexanes and stirred overnight, filtered and air dried to afford the title compound (33.2 g, 65% yield). 1 H NMR (CDCl 3 ) δ 1.14-1.28 (m, 2H), 1.30 (d, J=5 Hz, 1H), 1.38-1.52 (m, 2H), 1.91 (d, J=12 Hz, 2H), 2.00 (br s, 1H), 2.53 (tt, J=12, 3 Hz, 1H), 3.50-3.59 (m, 1H), 3.62 (s, 4H), 7.18-7.25 (m, 2H), 7.27-7.32 (m, 4H), 7.33-7.38 (m, 4H).

B. tert-Butyl 2-((trans-4-(dibenzylamino)cyclohexyl)oxy)acetate

trans-4-(Dibenzylamino)cyclohexanol (Intermediate 10A) (1.0 g, 3.4 mmol) and tert-butyl 2-bromoacetate (1.0 mL, 6.8 mmol) were stirred in DMF (5 mL) at 55° C. A 60% dispersion of NaH in mineral oil (0.27 g, 6.8 mmol) was added portion wise over 1 h. Additional tert-butyl 2-bromoacetate (1.00 mL, 6.8 mmol) and NaH (0.27 g, 6.8 mmol) were added portion wise over 1 h. The reaction was allowed to stir at 55° C. overnight, followed by careful quenching with water. The reaction was diluted with 1.0 N aqueous NaOH and extracted with EtOAc. The organic layer was washed with water (2×), followed by brine. The combined aqueous fractions were extracted with EtOAc and the combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 2-15% (3:1 ratio of EtOAc:EtOH in hexanes). The appropriate fractions were concentrated under reduced pressure to afford the title compound as a colorless oil (497 mg, 1.21 mmol). 1 H NMR (CDCl 3 ) δ 1.43-1.46 (m, 4H), 1.47 (s, 9H), 1.92 (d, J=12 Hz, 2H), 2.07-2.14 (m, 2H), 2.48-2.58 (m, 1H), 3.24-3.30 (m, 1H), 3.61 (s, 4H), 3.96 (s, 2H), 7.17-7.24 (m, 2H), 7.26-7.32 (m, 4H), 7.34-7.38 (m, 4H); LC-MS (LC-ES) M+H=410.

C. 2-((trans-4-(Dibenzylamino)cyclohexyl)oxy)acetic acid hydrochloride

tert-Butyl 2-((trans-4-(dibenzylamino)cyclohexyl)oxy)acetate (Intermediate 10B) (2.0 g, 4.9 mmol) was stirred in DCM (5.0 mL), and TFA (3 mL) was added. The reaction was stirred at room temperature for 1 h before concentrating under reduced pressure. The residue was taken up in 1,4-dioxane (5 mL), and 4.0 M HCl in dioxane (2 mL) was added and then stirred at 0° C. Diethyl ether (20 mL) was added and the resulting precipitate was stirred at the same temperature for ˜10 min before collecting by vacuum filtration. The solid was washed with diethyl ether providing the title compound as a white solid (2.03 g, 5.21 mmol). LC-MS (LC-ES) M+H=354.

D. 2-((trans-4-(Dibenzylamino)cyclohexyl)oxy)-N-methoxy-N-methylacetamide

2-((trans-4-(Dibenzylamino)cyclohexyl)oxy)acetic acid hydrochloride (Intermediate 10C) (2.0 g, 5.1 mmol) was dissolved in DMF (50 mL) followed by the addition of N,N-diisopropylethylamine (3 mL, 17.2 mmol) and HATU (2.34 g, 6.16 mmol). The reaction was stirred at room temperature for ca. 5 min, and N,O-dimethylhydroxylamine hydrochloride (0.751 g, 7.69 mmol) was added. The reaction was allowed to stir at room temperature overnight, diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organics were separated and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 50-90% EtOAc/heptanes. The appropriate fractions were concentrated under reduced pressure and solidified under high vacuum to afford the title compound as a yellow solid (1.74 g, 4.38 mmol). 1 H NMR (CDCl 3 ) δ 1.17-1.30 (m, 2H), 1.34-1.46 (m, 2H), 1.92 (d, J=12 Hz, 2H), 2.14 (d, J=11 Hz, 2H), 2.49-2.60 (m, 1H), 3.18 (s, 3H), 3.27-3.37 (m, 1H), 3.61 (s, 4H), 3.68 (s, 3H), 4.27 (s, 2H), 7.18-7.40 (m, 10H); LC-MS (LC-ES) M+H=398.

E. 1-Cyclopropyl-2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethanone

To 2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)-N-methoxy-N-methylacetamide (Intermediate 10D) (4.6 g, 12 mmol) in THF (15 mL) at 0° C. was added a 1.0 M solution of cyclopropylmagnesium bromide in 2-methylTHF (13 mL, 13 mmol). After 10 minutes, the reaction was warmed to room temperature. After 1 h, additional cyclopropylmagnesium bromide solution (2 mL, 2.0 mmol) was added. After another hour, the reaction was quenched with saturated aqueous NH 4 Cl (5 mL) and partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by brine. The combined aqueous washes were back extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 30-70% ethyl acetate in heptanes. The appropriate fractions were concentrated under reduced pressure to afford the title compound as an oil that turned to a pale yellow solid (3.62 g, 83%). 1 H NMR (CDCl 3 ) δ 0.92 (td, J=8, 4 Hz, 2H), 1.08 (quin, J=4 Hz, 2H), 1.18-1.32 (m, 2H), 1.34-1.47 (m, 2H), 1.94 (d, J=12 Hz, 2H), 2.11 (d, J=12 Hz, 2H), 2.15-2.23 (m, 1H), 2.55 (tt, J=12, 3 Hz, 1H), 3.20-3.30 (m, 1H), 3.61 (s, 4H), 4.17 (s, 2H), 7.22 (d, J=7 Hz, 2H), 7.27-7.32 (m, 4H), 7.33-7.40 (m, 4H); LC-MS (LC-ES) M+H=378.

F. Racemic 1-Cyclopropyl-2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethanol

To 1-cyclopropyl-2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethanone (Intermediate 10E) (1.0 g, 2.7 mmol) in THF (5 mL) at 0° C. was added a 1.0 M solution of LAH in diethyl ether (2.7 mL, 2.7 mmol). After 30 min, the reaction was warmed to room temperature for 2 hours, quenched with water (0.3 mL), 20% aqueous KOH (0.3 mL), then water (0.5 mL); and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 30-70% ethyl acetate in heptanes. The appropriate fractions were concentrated under reduced pressure to afford the title compound as a colorless oil (886 mg, 88% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 0.21 (dq, J=9, 5 Hz, 1H), 0.37 (dq, J=9, 5 Hz, 1H), 0.43-0.62 (m, 2H), 0.75-0.87 (m, 1H), 1.09-1.23 (m, 2H), 1.35-1.48 (m, 2H), 1.93 (d, J=12 Hz, 2H), 2.04-2.14 (m, 2H), 2.38 (d, J=3 Hz, 1H), 2.54 (tt, J=12, 3 Hz, 1H), 3.02 (tt, J=8, 3 Hz, 1H), 3.18-3.29 (m, 1H), 3.38 (t, J=9 Hz, 1H), 3.59 (d, J=3 Hz, 1H), 3.62 (s, 4H), 7.17-7.24 (m, 2H), 7.29 (t, J=8 Hz, 4H), 7.34-7.40 (m, 4H); LC-MS (LC-ES) M+H=380.

G. Racemic 2-(((trans)-4-Aminocyclohexyl)oxy)-1-cyclopropylethanol

1-Cyclopropyl-2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethanol (Intermediate 10F) (0.886 g, 2.33 mmol) and 20 wt % Pearlman's catalyst (0.164 g, 0.233 mmol) were stirred in ethanol (20 mL) and purged with hydrogen via balloon (3×) before stirring at room temperature overnight under a hydrogen atmosphere. The reaction was purged with nitrogen, filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (478 mg, quantitative yield). 1 H NMR (400 MHz, CD 3 OD) δ 0.22 (dq, J=9, 5 Hz, 1H), 0.38 (dq, J=9, 5 Hz, 1H), 0.44-0.61 (m, 2H), 0.79-0.92 (m, 1H), 1.06-1.19 (m, 2H), 1.24-1.40 (m, 2H), 1.90 (d, J=13 Hz, 2H), 2.00-2.11 (m, 2H), 2.73 (tt, J=11, 4 Hz, 1H), 3.04 (td, J=8, 3 Hz, 1H), 3.24-3.34 (m, 1H), 3.43 (d, J=9 Hz, 1H), 3.63 (dd, J=9, 3 Hz, 1H); LC-MS (LC-ES) M+H=200.

Intermediate 11: (trans)-N1-(Pyrimidin-2-yl)cyclohexane-1,4-diamine dihydrobromide

A. Benzyl ((trans)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate

To a microwave reaction vial with benzyl ((trans)-4-aminocyclohexyl)carbamate (600 mg, 2.4 mmol) in acetonitrile (8 mL) was added 2-chloropyrimidine (360 mg, 3.1 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol). The mixture was heated in a microwave (155° C.) for 6 h, the solvent was concentrated in vacuo and the residue purified on silica gel eluting with a 15%-80% (EtOAc/EtOH 3/1)-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.06-1.37 (m, 4H), 1.96-2.18 (m, 4H), 3.42-3.51 (m, 1H), 3.66-3.76 (m, 1H), 4.54-4.61 (m, 1H), 5.02 (s, 2H), 5.26-5.34 (m, 1H), 6.46 (t, J=5 Hz, 1H), 7.22-7.33 (m, 5H), 8.20 (d, J=5 Hz, 2H); LC-MS (LC-ES) M+H=327.

B. (trans)-N1-(Pyrimidin-2-yl)cyclohexane-1,4-diamine dihydrobromide

To benzyl ((trans)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate (Intermediate 11A) (200 mg, 0.61 mmol) was added 33% HBr in AcOH (4 mL, 24 mmol). The mixture was stirred at room temperature for 3 h and the solvent was removed in vacuo to give the title compound as a tan solid (287 mg, quantitative yield). 1 H NMR (400 MHz, CD 3 OD) δ 1.53-1.65 (m, 4H), 2.04-2.30 (m, 4H), 3.13-3.27 (m, 1H), 3.87-4.06 (m, 1H), 6.82-7.18 (m, 1H), 8.31-8.94 (m, 2H); LC-MS (LC-ES) M+H=193.

Intermediate 12: Racemic 1-(((trans)-4-Aminocyclohexyl)oxy)-2-cyclopropylpropan-2-ol

A. Racemic 2-Cyclopropyl-1-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)propan-2-ol

To 1-cyclopropyl-2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethanone (Intermediate 10E) (1.0 g, 2.7 mmol) in THF (8 mL) at 0° C. was added a 3.0 M solution of methylmagnesium chloride in diethyl ether (1 mL, 3.0 mmol). After 10 minutes, the mixture was warmed to room temperature for 2 h, quenched with saturated aqueous NH 4 Cl (5 mL) and partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by brine. The combined aqueous washes were back extracted with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 10-40% ethyl acetate in heptanes. The appropriate fractions were concentrated under reduced pressure to afford the title compound as an oil that turned to a pale yellow solid (0.95 g, 91%). 1 H NMR (CDCl 3 ) δ 0.31-0.36 (m, 3H), 0.41-0.46 (m, 1H), 0.82-0.93 (m, 1H), 1.07 (s, 3H), 1.09-1.23 (m, 2H), 1.34-1.49 (m, 2H), 1.92 (d, J=12 Hz, 2H), 2.07 (d, J=12 Hz, 2H), 2.54 (tt, J=12, 3 Hz, 1H), 3.20 (tt, J=11, 4 Hz, 1H), 3.30-3.37 (m, 2H), 3.62 (s, 4H), 7.19-7.24 (m, 2H), 7.29 (t, J=7 Hz, 4H), 7.34-7.39 (m, 4H); LC-MS (LC-ES) M+H=394.

B. Racemic 1-(((trans)-4-Aminocyclohexyl)oxy)-2-cyclopropylpropan-2-ol

2-Cyclopropyl-1-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)propan-2-ol (Intermediate 12A) (0.945 g, 2.40 mmol) and 20 wt % Pearlman's catalyst (0.169 g, 0.240 mmol) were stirred in ethanol (20 mL) and purged with hydrogen via balloon (3×) before stirring at room temperature overnight under a hydrogen atmosphere. The reaction was filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (470 mg, 92%). 1 H NMR (400 MHz, CDCl 3 ) δ 0.26-0.39 (m, 3H), 0.42-0.49 (m, 1H), 0.82-0.92 (m, 1H), 1.08-1.20 (m, 5H), 1.25-1.39 (m, 2H), 1.89 (d, J=11 Hz, 2H), 2.02 (d, J=11 Hz, 2H), 2.73 (tt, J=11, 4 Hz, 1H), 3.21-3.31 (m, 1H), 3.33-3.41 (m, 2H); LC-MS (LC-ES) M+H=214.

Intermediate 13: (trans)-N-(Azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide, trifluoroacetic acid salt

A. tert-Butyl 3-((trans)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)azetidine-1-carboxylate

To a DMF (8 mL) solution of (trans)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylic acid (Intermediate 4) (50 mg, 0.18 mmol) was added HATU (578 mg, 1.5 mmol)) and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol). After 5 minutes, tert-butyl 3-aminoazetidine-1-carboxylate (262 mg, 1.5 mmol) was added, and the mixture was stirred for 2 h, diluted with water and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 20%-60% EtOAc/EtOH (3:1) in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white foam (434 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.44 (s, 9H), 2.35-2.53 (m, 2H), 2.65-2.81 (m, 2H), 2.93-3.11 (m, 1H), 3.73 (dd, J=10, 5 Hz, 2H), 4.21-4.35 (m, 2H), 4.58-4.73 (m, 1H), 4.94 (s, 1H), 5.92-6.04 (m, 1H), 6.47 (s, 1H), 6.48-6.55 (m, 1H), 6.59-6.64 (m, 1H), 7.12 (dd, J=9, 6 Hz, 1H); LC-MS (LC-ES) M+H=431.

B. (trans)-N-(Azetidin-3-yl)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamide, trifluoroacetic acid salt

To a dichloromethane (2 mL) solution of tert-butyl 3-((trans)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)azetidine-1-carboxylate (Intermediate 13A) (430 mg, 1.0 mmol) was added HCl (4 M in dioxane) (4 mL, 16 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo to give a sticky oil which was triturated with ether to yield a white solid. This material was loaded onto a semi-prep HPLC (TFA as modifier) to afford the title compound. 1 H NMR (400 MHz, CD 3 OD) δ 2.39-2.50 (m, 2H), 2.66-2.75 (m, 2H), 3.10-3.22 (m, 1H), 4.11-4.22 (m, 2H), 4.24-4.37 (m, 2H), 4.56-4.74 (m, 1H), 4.89-4.96 (m, 1H), 6.64-6.72 (m, 3H), 7.10-7.20 (m, 1H); LC-MS (LC-ES) M+H=331.

Intermediate 14: trans-4-(3,3-Difluoroazetidin-1-yl)cyclohexanamine

A. Benzyl (trans-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)carbamate

3,3-Difluoroazetidine hydrochloride (0.593 g, 4.58 mmol) was added to benzyl (4-oxocyclohexyl)carbamate (1.03 g, 4.17 mmol) in 1,2-dichloroethane (21 mL) at room temperature and stirred for 5 minutes, followed by acetic acid (0.013 g, 0.21 mmol) and 4 Å molecular sieves (4.0 g). After 2 h, sodium triacetoxyborohydride (0.883 g, 4.17 mmol) was added, and the reaction mixture was stirred for 16 h. The reaction mixture was filtered through Celite®, saturated sodium bicarbonate added, extracted with DCM, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (2:3) to give the title compound (0.590 g, 42% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.97 (q, J=13 Hz, 2H), 1.14 (dq, J=13, 3 Hz, 2H), 1.68 (br d, J=12 Hz, 2H), 1.76 (br d, J=12 Hz, 2H), 2.03 (t, J=10 Hz, 1H), 3.16-3.30 (m, 1H), 3.96 (t, J=12 Hz, 4H), 4.98 (s, 2H), 7.18 (d, J=8 Hz, 1H), 7.26-7.38 (m, 5H); LC-MS (LC-ES) M+H=325.

B. trans-4-(3,3-Difluoroazetidin-1-yl)cyclohexanamine

Palladium on carbon (0.019 g, 0.18 mmol) was added to benzyl (trans-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)carbamate (Intermediate 14A) (0.590 g, 1.82 mmol) in MeOH (9 mL) at 25° C. under nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 3 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite® and concentrated to give the title compound (0.340 g, 93% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.88-1.02 (m, 4H), 1.54 (br s, 2H), 1.68-1.74 (m, 4H), 1.96-2.06 (m, 1H), 2.40-2.52 (m, 1H), 3.48 (t, J=12 Hz, 4H); LC-MS (LC-ES) M+H=191.

Intermediate 15: (S)-2-((trans-4-Aminocyclohexyl)amino)-3,3,3-trifluoropropan-1-ol

A. (S)-Benzyl (3-(trifluoromethyl)-1-oxa-4-azaspiro[4.5]decan-8-yl)carbamate

(S)-2-Amino-3,3,3-trifluoropropan-1-ol hydrochloride (0.676 g, 4.08 mmol) was added to benzyl (4-oxocyclohexyl)carbamate (1.01 g, 4.08 mmol) in benzene (41 mL) at room temperature and the reaction was heated with a Dean-Stark trap for 16 h. The reaction mixture was cooled, saturated sodium bicarbonate added, extracted with diethyl ether, dried over magnesium sulfate, filtered, and concentrated to give the title compound (1.52 g, 99% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.32-1.80 (m, 8H), 3.62-4.04 (m, 4H), 4.98 & 4.99 (s, 2H), 7.20 & 7.24 (d, J=8 Hz, 1H), 7.26-7.40 (m, 5H); LC-MS (LC-ES) M+H=359.

B. Benzyl (trans-4-(((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)carbamate

Sodium triacetoxyborohydride (0.899 g, 4.24 mmol) was added to benzyl ((3S)-3-(trifluoromethyl)-1-oxa-4-azaspiro[4.5]decan-8-yl)carbamate (Intermediate 15A) (1.52 g, 4.24 mmol) in 1,2-dichloroethane (21 mL) at room temperature, followed by acetic acid (0.013 g, 0.21 mmol). After 4 h, the reaction mixture was diluted with saturated sodium bicarbonate, extracted with DCM, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:1) to give the title compound (0.771 g, 48% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.02 (q, J=13 Hz, 2H), 1.14 (q, J=13 Hz, 2H), 1.72-1.92 (m, 5H), 2.36-2.48 (m, 1H), 3.14-3.28 (m, 2H), 3.40-3.50 (m, 1H), 3.54-3.64 (m, 1H), 4.96 (t, J=6 Hz, 1H), 4.98 (s, 2H), 7.15 (d, J=8 Hz, 1H), 7.26-7.38 (m, 5H); LC-MS (LC-ES) M+H=361.

C. (S)-2-((trans-4-Aminocyclohexyl)amino)-3,3,3-trifluoropropan-1-ol

Palladium on carbon (0.023 g, 0.21 mmol) was added to benzyl (trans-4-(((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)carbamate (Intermediate 15B) (0.771 g, 2.14 mmol) in MeOH (7 mL) at 25° C. under a nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 16 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (0.504 g, 99% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.92-1.06 (m, 4H), 1.46-1.88 (m, 7H), 2.36-2.50 (m, 2H), 3.16-3.28 (m, 1H), 3.40-3.50 (m, 1H), 3.54-3.64 (m, 1H), 4.97 (br s, 1H); LC-MS (LC-ES) M+H=227.

Intermediate 16: Racemic 1-(1,1-Difluoropropan-2-yl)piperidin-4-amine

A. Racemic Benzyl (1-(1,1-difluoropropan-2-yl)piperidin-4-yl)carbamate

1,1-Difluoropropan-2-one (0.608 g, 6.47 mmol) was added to benzyl piperidin-4-ylcarbamate (1.01 g, 4.31 mmol) in 1,2-dichloroethane (22 mL). After 5 min, acetic acid (0.013 g, 0.21 mmol) and 4 Å molecular sieves (4.0 g) were added. After 2 h, sodium triacetoxyborohydride (0.914 g, 4.31 mmol) was added, and the reaction mixture was stirred for 20 h. The reaction mixture was filtered through Celite®, saturated sodium bicarbonate added, extracted with DCM, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:2 to 2:3) to give the title compound (0.868 g, 61% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.95-1.10 (m, 3H), 1.28-1.39 (m, 2H), 1.67-1.72 (m, 2H), 2.27-2.40 (m, 2H), 2.49-2.52 (m, 1H), 2.71-2.80 (m, 2H), 2.82-2.98 (m, 1H), 3.19-3.31 (m, 1H), 4.99 (s, 2H), 5.99 (dt, J=8, 56 Hz, 1H), 7.25-7.38 (m, 5H); LC-MS (LC-ES) M+H=313.

B. Racemic 1-(1,1-difluoropropan-2-yl)piperidin-4-amine

Palladium on carbon (0.030 g, 0.28 mmol) was added to benzyl (1-(1,1-difluoropropan-2-yl)piperidin-4-yl)carbamate (Intermediate 16A) (0.868 g, 2.78 mmol) in MeOH (14 mL) at 25° C. under nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 2 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite® and concentrated to give the title compound (0.452 g, 87% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.93-1.00 (m, 3H), 1.10-1.21 (m, 2H), 1.60-1.64 (m, 2H), 2.02 (br s, 2H), 2.24-2.34 (m, 2H), 2.45-2.49 (m, 1H), 2.68-2.78 (m, 2H), 2.83-2.95 (m, 1H), 5.99 (dt, J=8, 56 Hz, 1H); LC-MS (LC-ES) M+H=179.

Intermediate 17: Racemic trans-N1-(1,1-Difluoropropan-2-yl)cyclohexane-1,4-diamine

A. Racemic Benzyl (trans-4-((1,1-difluoropropan-2-yl)amino)cyclohexyl)carbamate

1,1-Difluoropropan-2-one (3.13 g, 33.3 mmol) was added to benzyl (trans-4-aminocyclohexyl)carbamate (7.52 g, 30.3 mmol) in 1,2-dichloroethane (151 mL). After 5 min, added acetic acid (0.091 g, 1.5 mmol) and 4 Å molecular sieves (20.0 g), and the reaction was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (6.42 g, 30.3 mmol) was added, and the reaction mixture was stirred for 20 h. The reaction mixture was filtered through Celite®, saturated sodium bicarbonate added, extracted with DCM, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:1) to give the title compound (8.41 g, 81% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.99 (d, J=7 Hz, 3H), 0.94-1.06 (m, 2H), 1.08-1.22 (m, 2H), 1.45 (br s, 1H), 1.70-1.88 (m, 4H), 2.36-2.48 (m, 1H), 2.86-3.00 (m, 1H), 3.14-3.28 (m, 1H), 4.97 (s, 2H), 5.74 (dt, J=56, 4 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 7.26-7.38 (m, 5H); LC-MS (LC-ES) M+H=327.

B. Racemic trans-N1-(1,1-Difluoropropan-2-yl)cyclohexane-1,4-diamine

Palladium on carbon (0.137 g, 1.29 mmol) was added to benzyl (trans-4-((1,1-difluoropropan-2-yl)amino)cyclohexyl)carbamate (Intermediate 17A) (8.41 g, 25.8 mmol) in MeOH (51.5 mL) at 25° C. under nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 6 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (5.05 g, 97% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.90-1.04 (m, 4H), 0.99 (d, J=7 Hz, 3H), 1.30-1.60 (m, 3H), 1.62-1.84 (m, 4H), 2.34-2.48 (m, 2H), 2.86-3.00 (m, 1H), 5.73 (dt, J=56, 4 Hz, 1H); LC-MS (LC-ES) M+H=193.

Intermediate 18: Racemic (R,S)-1-((trans)-4-Aminocyclohexyl)ethanol hydrochloride

A. trans-Methyl 4-((tertbutoxycarbonyl)amino)cyclohexanecarboxylate

To (trans)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.5 mg, 13 mmol) in tert-butanol (25 mL) was added diphenyl phosphorazidate (3.88 g, 14 mmol) and triethylamine (1.97 mL, 14 mmol). The mixture was heated at 60° C. for 1 h and then at reflux overnight. After cooling to room temperature, the mixture was quenched into ice water and extracted with EtOAc. The combined organics were washed with sat. NaHCO 3 and brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was dissolved in MeOH (6 mL) and to this was added water (18 mL). After stirring for ca. 1 h on ice, the resulting solid was collected by filtration, and washed with 3:1 water:MeOH, and hexanes to give the title compound as a white solid (2.32 g, 67% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.05-1.20 (m, 2H), 1.25-1.44 (m, 11H), 1.72-1.91 (m, 4H), 2.17 (tt, J=12, 3 Hz, 1H), 3.06-3.21 (m, 1H), 3.56 (s, 3H), 6.72 (d, J=8 Hz, 1H).

B. tert-Butyl ((trans)-4-(hydroxymethyl)cyclohexyl)carbamate

To a solution of (trans)-methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (Intermediate 18A) (1.5 g, 5.8 mmol) in EtOH (24 mL) and THF (2.7 mL), cooled on ice, was added calcium chloride (1.29 g, 11.7 mmol) portion wise to give a milky suspension. NaBH 4 (882 mg, 23.3 mmol) was then added portion wise over ca. 25 min and the reaction was stirred on ice for 1 h. The bath was removed and the mixture was allowed to stir at room temperature overnight. The reaction was cooled to 10° C. and to this was added 5% aqueous K 2 CO 3 (5.4 mL) dropwise, to give a pH of ca. 11. A white precipitate formed and was isolated by filtration. The solid was stirred with EtOAc (50 mL) and water (14 mL). The layers were separated and the organic layer was washed with 0.5 M aqueous HCl (5 mL), water and brine, dried over MgSO 4 , filtered, and concentrated to give the title compound (474 mg) as a white solid. The initial filtrate was concentrated, then dilute with saturated aqueous NH 4 Cl and extracted with EtOAc (3×). Combined organics were washed with brine and dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (724 mg) as a white solid. Total isolated product was 1.19 g (89% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.78-0.93 (m, 2H), 1.01-1.15 (m, 2H), 1.35 (s, 9H), 1.64-1.80 (m, 4H), 3.10 (d, J=8 Hz, 1H), 3.16 (t, J=6 Hz, 2H), 4.33 (t, J=5 Hz, 1H), 6.64 (d, J=8 Hz, 1H).

C. tert-Butyl ((trans)-4-formylcyclohexyl)carbamate

To a solution of tert-butyl ((trans)-4-(hydroxymethyl)cyclohexyl)carbamate (Intermediate 18B) (375 mg, 1.64 mmol) in DCM (9 mL) and DMSO (2.8 mL), cooled on ice, was added N,N-diisopropylethylamine (1.14 mL, 6.54 mmol), followed by pyridine sulfur trioxide (1041 mg, 6.54 mmol) dissolved in DMSO (2.8 mL). The bath was removed and the reaction stirred at room temperature for 15 min. The mixture was partitioned between Et 2 O and 1 N aqueous HCl. The organic phase was washed with 1 N HCl, water, and brine, dried over MgSO 4 , filtered, and concentrated to give the title compound as a white solid (343 mg, 92% yield), which was used without purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.10-1.23 (m, 4H), 1.35 (s, 9H), 1.73-1.93 (m, 4H), 2.07-2.19 (m, 1H), 3.05-3.20 (m, 1H), 6.74 (d, J=7 Hz, 1H), 9.53 (s, 1H).

D. Racemic tert-Butyl ((trans)-4-((R,S)-1-hydroxyethyl)cyclohexyl)carbamate

To a solution of tert-butyl ((trans)-4-formylcyclohexyl)carbamate (Intermediate 18C) (70 mg, 0.31 mmol) in THF (4 mL), cooled to −78° C., was added methylmagnesium iodide (0.23 mL, 0.68 mmol, 3 M in THF) dropwise over ca. 2 min, and the reaction was stirred at −78° C. for 30 min. The reaction was poured into saturated NH 4 Cl and extracted with TBME. The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc-hexanes gradient) to afford the title compound as a glass (15 mg, 20% yield).

A second reaction was run with the following procedure.

To a solution of tert-butyl ((trans)-4-formylcyclohexyl)carbamate (Intermediate 18C) (100 mg, 0.44 mmol) in THF (4 mL), cooled to −78° C., was added methylmagnesium bromide (0.18 mL, 0.55 mmol, 3 M in THF) dropwise over ca. 2-3 minutes, and the reaction was stirred at −78° C. for 30 min. The reaction was poured into saturated NH 4 Cl and extracted with TBME. The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc-hexanes gradient) to afford the title compound as a white foam (27 mg, 25% yield). This product and the above were combined to be used in the next step. 1 H NMR (400 MHz, 400 MHz, CD 3 SOCD 3 ) δ 0.87-1.10 (m, 7H), 1.35 (s, 9H), 1.57 (d, J=10 Hz, 1H), 1.67-1.85 (m, 4H), 3.08 (d, J=7 Hz, 1H), 3.25-3.46 (m, 2H), 6.62 (d, J=8 Hz, 1H).

E. Racemic (R,S)-1-((trans)-4-Aminocyclohexyl)ethanol hydrochloride

To tert-butyl ((trans)-4-((R,S)-1-hydroxyethyl)cyclohexyl)carbamate (Intermediate 18D) (40 mg, 0.16 mmol) was added 4 N HCl in dioxane (5 mL). The mixture was stirred at room temperature for 3.5 h and concentrated to give the title compound as a glass (33 mg, 112% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.99 (d, J=6 Hz, 3H), 1.06 (d, J=7 Hz, 2H), 1.20-1.29 (m, 2H), 1.63 (d, J=12 Hz, 1H), 1.84 (d, J=13 Hz, 1H), 1.93 (d, J=12 Hz, 2H), 2.85 (d, J=5 Hz, 1H), 3.46 (dd, J=12, 4 Hz, 1H), 3.62-3.74 (m, 1H).

Intermediate 19: Racemic ((trans)-4-Aminocyclohexyl)(cyclopropyl)methanol

A. (trans)-Methyl 4-(dibenzylamino)cyclohexanecarboxylate

To a mixture of (trans)-methyl 4-aminocyclohexanecarboxylate hydrochloride (1.7 g, 8.78 mmol), acetonitrile (30 mL), and K 2 CO 3 (4.85 g, 35.1 mmol) was added benzyl bromide (3.75 g, 22.0 mmol). The reaction was heated at 80° C. overnight, cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc-hexanes gradient to afford the title compound as a white solid (1.55 g, 52% yield). 1 H NMR (CDCl 3 ) δ 1.28-1.43 (m, 4H), 1.54 (s, 3H), 1.92-2.04 (m, 4H), 2.13-2.21 (m, 1H), 2.47-2.55 (m, 1H), 3.60-3.62 (m, 4H), 7.16-7.36 (m, 10H).

B. (trans)-4-(Dibenzylamino)cyclohexanecarboxylic acid

To a mixture of (trans)-methyl 4-(dibenzylamino)cyclohexanecarboxylate (Intermediate 19A) (1 g, 2.96 mmol) in THF (10 mL), methanol (5 mL) and water (5 mL), LiOH (0.213 g, 8.89 mmol) was added. After 15 hours, the mixture was concentrated under reduced pressure. The residue was taken up in water and acidified with 6.0 N aqueous HCl until a white precipitate formed. The precipitate was collected by filtration and dried under vacuum to give the title compound (791 mg, 83% yield). This procedure was repeated on multiple occasions. Representative 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.07-1.24 (m, 2H), 1.31-1.49 (m, 2H), 1.85 (d, J=11 Hz, 2H), 1.93 (d, J=12 Hz, 2H), 2.05-2.19 (m, 1H), 2.30-2.45 (m, 1H), 3.58 (s, 4H), 7.14-7.24 (m, 2H), 7.24-7.42 (m, 8H), 11.98 (br s, 1H); LC-MS (LC-ES) M+H=324.

C. (trans)-4-(Dibenzylamino)-N-methoxy-N-methylcyclohexanecarboxamide

(trans)-4-(Dibenzylamino)cyclohexanecarboxylic acid (Intermediate 19B) (0.79 g, 2.4 mmol) was dissolved in DMF (20 mL) followed by the addition of N,N-diisopropylethylamine (1.3 mL, 7.3 mmol) and HATU (1.11 g, 2.93 mmol). The reaction was stirred at room temperature for ca. 10 min, and N,O-dimethylhydroxylamine hydrochloride (0.286 g, 2.93 mmol) was added. After 15 h, the reaction was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organics were separated and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a 30-70% EtOAc/heptanes gradient. The appropriate fractions were concentrated under reduced pressure and solidified under high vacuum to afford the title compound as a white solid (728 mg, 81%). 1 H NMR (CDCl 3 ) δ 1.39-1.57 (m, 4H), 1.84-1.92 (m, 2H), 2.01 (d, J=9 Hz, 2H), 2.57-2.69 (m, 2H), 3.18 (s, 3H), 3.67 (s, 4H), 3.70 (s, 3H), 7.20-7.26 (m, 2H), 7.31 (t, J=7 Hz, 4H), 7.36-7.43 (m, 4H); LC-MS (LC-ES) M+H=367.

D. Cyclopropyl((trans)-4-(dibenzylamino)cyclohexyl)methanone

To (trans)-4-(dibenzylamino)-N-methoxy-N-methylcyclohexanecarboxamide (Intermediate 19C) (0.275 g, 0.75 mmol) in THF (1.5 mL) at 0° C. was added a 1.0 M solution of cyclopropylmagnesium bromide in 2-methylTHF (0.75 mL, 0.75 mmol). After 10 minutes, the mixture was warmed to room temperature and stirred for 2 h. Additional cyclopropylmagnesium bromide solution (0.75 mL, 0.75 mmol) was added and the mixture was stirred for 1 h, then quenched with saturated aqueous NH 4 Cl (5 mL) and partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by brine. The combined aqueous washes were back extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil (268 mg, quantitative). 1 H NMR (CDCl 3 ) δ 0.82 (dq, J=7, 4 Hz, 2H), 0.93-0.99 (m, 2H), 1.25-1.37 (m, 2H), 1.38-1.50 (m, 2H), 1.89-1.96 (m, 1H), 2.01 (d, J=11 Hz, 4H), 2.42 (t, J=12 Hz, 1H), 2.53 (t, J=12 Hz, 1H), 3.64 (s, 4H), 7.17-7.24 (m, 2H), 7.27-7.33 (m, 4H), 7.34-7.40 (m, 4H); LC-MS (LC-ES) M+H=348.

E. Racemic Cyclopropyl((trans)-4-(dibenzylamino)cyclohexyl)methanol

To cyclopropyl((trans)-4-(dibenzylamino)cyclohexyl)methanone (Intermediate 19D) (0.260 g, 0.75 mmol) in THF (1.5 mL) at 0° C. was added a 1.0 M solution of lithium aluminum hydride in diethyl ether (0.85 mL, 0.85 mmol). After 20 min, the mixture was warmed to room temperature for 1 hour; quenched with water (0.15 mL), 10% aqueous NaOH (0.15 mL), then water (0.3 mL); and partitioned between water and ethyl acetate. After 10 min, sodium sulfate was added, solids were filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a 10-50% ethyl acetate in heptanes gradient. The appropriate fractions were concentrated under reduced pressure to afford the title compound (145 mg, 55% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 0.20 (d, J=2 Hz, 2H), 0.41-0.49 (m, 1H), 0.50-0.58 (m, 1H), 0.82-0.94 (m, 1H), 0.97-1.14 (m, 2H), 1.34-1.53 (m, 4H), 1.88-2.02 (m, 4H), 2.46-2.57 (m, 2H), 3.65 (s, 4H), 7.21 (q, J=7 Hz, 2H), 7.29 (t, J=7 Hz, 4H), 7.39 (d, J=7 Hz, 4H).

F. Racemic ((trans)-4-Aminocyclohexyl)(cyclopropyl)methanol

Cyclopropyl((trans)-4-(dibenzylamino)cyclohexyl)methanol (Intermediate 19E) (0.145 g, 0.42 mmol) and 20 wt % Pearlman's catalyst (0.029 g, 0.04 mmol) were stirred in ethanol (4 mL) and purged with hydrogen via balloon (3×) before stirring under a hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound as an oil (68 mg, 97%). LC-MS (LC-ES) M+H=170.

Intermediate 20: Racemic 2-((trans)-4-Aminocyclohexyl)-1,1,1-trifluoropropan-2-ol

A. 1-((trans)-4-(Dibenzylamino)cyclohexyl)ethanone

To (trans)-4-(dibenzylamino)-N-methoxy-N-methylcyclohexanecarboxamide (Intermediate 19C) (0.395 g, 1.08 mmol) in THF (2.5 mL) at 0° C. was added a 3.0 M solution of methylmagnesium bromide in diethyl ether (0.36 mL, 1.1 mmol). After 10 minutes, the mixture was warmed to room temperature, stirred for 2 h, quenched with saturated aqueous NH 4 Cl and stirred 10 min. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by brine. The combined aqueous washes were back extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a colorless oil that slowly crystallized (345 mg, 100%). 1 H NMR (CDCl 3 ) δ 1.21-1.33 (m, 2H), 1.36-1.49 (m, 2H), 1.98 (t, J=11 Hz, 4H), 2.11 (s, 3H), 2.21-2.31 (m, 1H), 2.52 (t, J=11 Hz, 1H), 3.64 (s, 4H), 7.19-7.25 (m, 2H), 7.30 (t, J=7 Hz, 4H), 7.35-7.40 (m, 4H); LC-MS (LC-ES) M+H—CH 3 CO=280.

B. Racemic 2-((trans)-4-(Dibenzylamino)cyclohexyl)-1,1,1-trifluoropropan-2-ol

To 1-((trans)-4-(dibenzylamino)cyclohexyl)ethanone (Intermediate 20A) (0.34 g, 1.1 mmol) and cesium fluoride (0.16 g, 1.1 mmol) in THF (2.25 mL) at 0° C. was slowly added trimethyl(trifluoromethyl)silane (0.39 mL, 2.6 mmol). After 1 hour, a 1.0 M solution of TBAF in THF (1.27 mL, 1.27 mmol) was added. The mixture was stirred for 1 hour, diluted with ethyl acetate and washed with water, followed by brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to an orange oil that was purified by silica gel chromatography eluting with 3% ethyl acetate in heptanes. Fractions recovered were concentrated under reduced pressure to the title compound as a white solid (271 mg, 66%). 1 H NMR (CDCl 3 ) δ 0.90-1.09 (m, 2H) 1.11-1.66 (m, 6H), 1.81-2.02 (m, 4H), 2.39-2.50 (m, 1H), 3.53-3.68 (m, 4H), 7.15-7.44 (m, 10H); LC-MS (LC-ES) M+H=392.

C. Racemic 2-((trans)-4-Aminocyclohexyl)-1,1,1-trifluoropropan-2-ol

2-((trans)-4-(Dibenzylamino)cyclohexyl)-1,1,1-trifluoropropan-2-ol (Intermediate 20B) (0.27 g, 0.69 mmol) and 20 wt % palladium hydroxide on carbon (0.097 g, 0.14 mmol) were stirred in ethanol (6 mL) and purged with hydrogen via balloon (3×) before stirring under a hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite® and rinsed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound as an oil (136 mg, 93%). 1 H NMR (CD 3 OD) δ 1.02-1.28 (m, 7H), 1.51-1.61 (m, 1H), 1.79-2.00 (m, 4H), 2.51-2.62 (m, 1H); LC-MS (LC-ES) M+H=212.

Intermediate 21: 3-Amino-1-methylcyclobutanol hydrochloride

A. Methylenecyclobutanecarboxylic acid

Potassium hydroxide (12.29 g, 219 mmol) was added to 3-methylenecyclobutanecarbonitrile (5.10 g, 54.8 mmol) in EtOH (27 mL) and water (27 mL) at room temperature, and the reaction mixture was heated at reflux for 16 h. After cooling, the EtOH was removed under vacuum, ice was added, and the reaction mixture was acidified to pH=1 with concentrated hydrochloric acid. The reaction mixture was extracted with EtOAc, dried over magnesium sulfate, filtered, and concentrated to give the title compound (6.37 g, 99% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.82 (dt, J=8, 2 Hz, 4H), 3.04 (p, J=8 Hz, 1H), 4.76 (p, J=2 Hz, 2H), 12.20 (br s, 1H); LC-MS (LC-ES) M−H=111.

B. tert-Butyl (3-methylenecyclobutyl)carbamate

Triethylamine (11.9 mL, 85 mmol) was added to 3-methylenecyclobutanecarboxylic acid (Intermediate 21A) (6.37 g, 56.8 mmol) in tert-butanol (57 mL) at room temperature, followed by diphenyl phosphoryl azide (14.7 mL, 68.2 mmol). The reaction mixture was heated at 85° C. under nitrogen for 17 h, quenched with water and concentrated. The residue was taken up in diethyl ether, washed with 10% citric acid followed by saturated sodium bicarbonate, the organic layer dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:9) to give the title compound (6.08 g, 56% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.36 (s, 9H), 2.54-2.64 (m, 2H), 2.76-2.86 (m, 2H), 3.92 (h, J=8 Hz, 1H), 4.76 (p, J=2 Hz, 2H), 7.23 (d, J=7 Hz, 1H).

C. tert-Butyl 1-oxaspiro[2.3]hexan-5-ylcarbamate

3-Chloroperbenzoic acid (6.30 g, 36.5 mmol) was added to tert-butyl (3-methylenecyclobutyl)carbamate (Intermediate 21B) (6.08 g, 33.2 mmol) in DCM (111 mL) at 0° C. After 4 h, the reaction mixture was washed with 10% sodium sulfite followed by saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:4 to 2:3) to give a 1:1 mixture of tert-butyl 1-oxaspiro[2.3]hexan-5-ylcarbamate (5.34 g, 77% yield) and recovered starting material (0.98 g, 16% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.37 & 1.37 (s, 9H), 2.30-2.40 (m, 2H), 2.44-2.54 (m, 2H), 2.62 (s, 1H), 2.66 (s, 1H), 3.83 (h, J=8 Hz, 0.5H), 3.94-4.06 (m, 0.5H), 7.24 (d, J=7 Hz, 0.5H), 7.34 (d, J=6 Hz, 0.5H).

D. tert-Butyl (3-hydroxy-3-methylcyclobutyl)carbamate

Lithium triethylborohydride (34.8 mL, 34.8 mmol) in THF (1.0 M) was added to tert-butyl 1-oxaspiro[2.3]hexan-5-ylcarbamate (Intermediate 21C) (5.34 g, 26.8 mmol) in THF (89 mL) at 0° C. under nitrogen. After 3 h, reaction mixture was quenched with water, solid potassium carbonate was added, then extracted with diethyl ether, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (2:3 to 1:1) to give the title compound (5.36 g, 94% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.17 (s, 1.5H), 1.19 (s, 1.5H), 1.35 (s, 9H), 1.78-1.92 (m, 2H), 2.08-2.18 (m, 2H), 3.46 (h, J=8 Hz, 0.5H), 3.99 (h, J=8 Hz, 0.5H), 4.70 (br s, 0.5H), 4.83 (br s, 0.5H), 7.00 (d, J=6 Hz, 1H); LC-MS (ES-MS) M+H=202.

E. 3-Amino-1-methylcyclobutanol hydrochloride

4.0 M Hydrochloric acid in dioxane (33.3 mL, 133 mmol) was added to tert-butyl (3-hydroxy-3-methylcyclobutyl)carbamate (Intermediate 21D) (5.36 g, 26.6 mmol) in MeOH (33 mL) at room temperature. After 16 h, the reaction mixture was concentrated to give the title compound (3.83 g, 99% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.22 (s, 1.5H), 1.25 (s, 1.5H), 2.04-2.14 (m, 2H), 2.14-2.26 (m, 2H), 3.15 (s, 0.5H), 3.20-3.32 (m, 0.5H), 3.56 (s, 0.5H), 3.66-3.78 (m, 0.5H), 8.09 (br s, 3H); LC-MS (LC-ES) M+H=102.

Intermediate 22: 2-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)-N-methoxy-N-methylthiazole-4-carboxamide

A. 2-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)thiazole-4-carboxylic acid

To a solution of ethyl 2-((trans)-3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)thiazole-4-carboxylate (Example 31) (60 mg, 0.14 mmol) in THF (5 mL) was added LiOH (13 mg, 0.56 mmol) in water (2.5 mL). After 1 hour, the mixture was adjusted to pH=4 with aqueous citric acid. The mixture was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (119 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.30-2.40 (m, 2H), 2.61-2.71 (m, 2H), 3.05-3.12 (m, 1H), 4.82-4.93 (m, 1H), 6.73-6.80 (m, 2H), 7.02 (t, J=76 Hz, 1H), 7.19-7.22 (m, 1H), 7.99 (s, 1H); LC-MS (LC-ES) M+H=403.

B. 2-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)-N-methoxy-N-methylthiazole-4-carboxamide

2-((trans)-3-(2-(Difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxamido)thiazole-4-carboxylic acid (Intermediate 22A) (55 mg, 0.14 mmol) was dissolved in DMF (4 mL) followed by the addition of N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) and HATU (62 mg, 0.16 mmol). The reaction was stirred at room temperature for ca. 5 min, and N,O-dimethylhydroxylamine hydrochloride (16 mg, 0.16 mmol) was added. After 3 h, the reaction was quenched with water, extracted with EtOAc (3×), and the combined organic extracts dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with a 0%-100% EtOAc-EtOH (3:1) in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (16 mg, 26%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.36-2.42 (m, 2H), 2.49 (s, 3H), 2.72-2.80 (m, 2H), 3.28 (s, 3H), 3.37-3.44 (m, 1H), 4.90-5.07 (m, 1H), 6.76-6.82 (m, 1H), 6.85-6.89 (m, 1H), 7.05 (t, J=76 Hz, 1H), 7.20-7.25 (m, 1H), 7.76 (s, 1H); LC-MS (LC-ES) M+H=446.

Intermediate 23: 1-(((trans)-4-Aminocyclohexyl)oxy)-2-methylpropan-2-ol

A. 1-((trans-4-(Dibenzylamino)cyclohexyl)oxy)-2-methylpropan-2-ol

tert-Butyl 2-((trans-4-(dibenzylamino)cyclohexyl)oxy)acetate (Intermediate 10B) (0.40 g, 0.98 mmol) was stirred in THF (2.5 mL) under nitrogen at 0° C., then a 3.0 M solution of methylmagnesium bromide (0.80 mL, 2.4 mmol) in diethyl ether was added. The reaction was stirred at room temperature for 3 h then quenched with saturated aqueous NH 4 Cl (3 mL) and stirred at room temperature overnight. The reaction was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate, water (2×), and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient from 5-15% ((3:1 EtOAc:EtOH) in hexanes), providing a colorless oil that solidified over time to afford the title compound (0.168 g, 47%). 1 H NMR (CDCl 3 ) δ 1.09-1.22 (m, 8H), 1.33-1.47 (m, 2H), 1.88-1.97 (m, 2H), 2.04-2.11 (m, 2H), 2.53 (tt, J=12, 3 Hz, 1H), 3.19 (tt, J=11, 4 Hz, 1H), 3.24 (s, 2H), 3.61 (s, 4H), 7.18-7.24 (m, 2H), 7.26-7.33 (m, 4H), 7.34-7.39 (m, 4H); LC-MS (LC-ES) M−H=368.

B. 1-(((trans)-4-Aminocyclohexyl)oxy)-2-methylpropan-2-ol

A mixture of 1-((trans-4-(dibenzylamino)cyclohexyl)oxy)-2-methylpropan-2-ol (Intermediate 23A) (620 mg, 1.69 mmol) and palladium hydroxide on carbon (300 mg, 2.14 mmol) in EtOH (5 mL) was hydrogenated at 55 psi (Fisher-Porter apparatus) for 2 h. The reaction mixture was filtered through a plug of Celite®. The catalyst was washed with MeOH and DCM. The filtrate was concentrated to dryness and dried under high vacuum to give the title compound as a grey solid (306 mg). 1 H NMR (CDCl 3 ) δ 1.07-1.35 (m, 4H), 1.17 (s, 6H), 1.92 (m, 2H), 2.02 (m, 2H), 2.45 (br s, 3H), 2.78 (m, 1H), 3.25 (m, 3H).

Intermediate 24: 6-(3-Aminoazetidin-1-yl)nicotinamide dihydrochloride

A. tert-Butyl (1-(5-carbamoylpyridin-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate (220 mg, 1.23 mmol) in acetonitrile (2 mL) with a small amount of NMP to facilitate solubility, 6-chloronicotinamide (200 mg, 1.28 mmol) was added, followed by N,N-diisopropylethylamine (0.22 mL, 1.3 mmol). The mixture was heated in a microwave at 130° C. for 2 h, cooled, and the resulting precipitate was collected by filtration to give the title compound (140 mg, 38%). 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 3.88-3.95 (m, 2H), 4.38 (t, J=8 Hz, 2H), 4.50-4.59 (m, 1H), 6.43 (d, J=9 Hz, 1H), 8.00 (dd, J=9, 2 Hz, 1H), 8.59 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=293.

B. 6-(3-Aminoazetidin-1-yl)nicotinamide dihydrochloride

To tert-butyl (1-(5-carbamoylpyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 24A) (140 mg, 0.48 mmol) in methanol (3 mL), 4 M HCl in dioxane (2 mL, 8 mmol) was added. The mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo to give a solid, which was triturated with EtOAc to give the title compound (124 mg, 98%). 1 H NMR (400 MHz, CD 3 OD) δ 4.39-4.48 (m, 1H), 4.49-4.57 (m, 2H), 4.73-4.85 (m, 2H), 7.06 (d, J=9 Hz, 1H), 8.44 (dd, J=9, 2 Hz, 1H), 8.52 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=192.

Intermediate 25: (trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylate

Triphenylphosphine (9.72 g, 37.0 mmol) was added to a solution of benzo[d]thiazol-4-ol (4.00 g, 26.5 mmol) in tetrahydrofuran (80 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (4.13 g, 31.7 mmol) was added, followed by the dropwise addition of DIAD (7.20 mL, 37.0 mmol). The reaction mixture was then warmed to room temperature, stirred over the weekend, and concentrated. The remaining material was purified on silica gel eluting with a 15%-60% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (6.72 g, 90%) which contained about 1.1 equivalent of reduced DIAD contaminant. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.51-2.67 (m, 2H), 2.75 (td, J=7, 4 Hz, 2H), 3.10-3.19 (m, 1H), 3.67 (s, 3H), 5.03-5.10 (m, 1H), 6.68 (d, J=8 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 8.84 (s, 1H); LC-MS (LC-ES) M+H=264.

B. (trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylate (Intermediate 25A) (400 mg, 1.5 mmol) in THF (20 mL) and water (7 mL) was added LiOH (91 mg, 3.8 mmol). The reaction mixture was stirred at room temperature for 2 h. A portion of the solvents were removed in vacuo, and the remainder was partitioned between EtOAc and water. The aqueous layer was separated and adjusted to pH=4 with the addition of aqueous citric acid. The resulting white precipitate was collected by filtration, washed with water and air dried to give the title compound (140 mg, 37%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.17-2.34 (m, 2H), 2.44-2.57 (m, 2H), 3.11-3.22 (m, 1H), 4.72-4.89 (m, 1H), 6.88 (d, J=8 Hz, 1H), 7.38-7.44 (m, 1H), 7.71 (d, J=8 Hz, 1H), 9.27 (s, 1H); LC-MS (LC-ES) M+H=250.

C. (trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid, lithium salt

To a solution of (trans)-methyl 3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylate (Intermediate 25A) (3.48 g, 13.2 mmol) in THF (40 mL) and water (15 mL) was added lithium hydroxide (0.790 g, 33.0 mmol). After 2 h, the solvents were removed in vacuo and the resulting solid was triturated with ether affording the title compound (5.7 g, quantitative) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.20 (dd, J=7, 3 Hz, 2H), 2.61 (dt, J=6, 3 Hz, 2H), 2.65-2.74 (m, 1H), 4.96-5.09 (m, 1H), 6.80 (d, J=8 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 9.23 (s, 1H); LC-MS (LC-ES) M+H-Li=250.

Intermediate 26: 6-(3-Aminoazetidin-1-yl)-N-methylnicotinamide dihydrochloride

A. tert-Butyl (1-(5-(methylcarbamoyl)pyridin-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate (202 mg, 1.07 mmol) in acetonitrile (2 mL) with a small amount of NMP to facilitate solubility, 6-chloro-N-methylnicotinamide (200 mg, 1.17 mmol) was added, followed by N,N-diisopropylethylamine (0.41 mL, 2.3 mmol). The mixture was heated in a microwave at 130° C. for 2 h, cooled, and the resulting precipitate was collected by filtration to give the title compound (124 mg, 35%). 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 2.88 (s, 3H), 3.92 (dd, J=8, 4 Hz, 2H), 4.36 (t, J=8 Hz, 2H), 4.48-4.55 (m, 1H), 6.43 (d, J=9 Hz, 1H), 8.00 (dd, J=9, 2 Hz, 1H), 8.52 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=307.

B. 6-(3-Aminoazetidin-1-yl)-N-methylnicotinamide dihydrochloride

To tert-butyl (1-(5-carbamoylpyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 26A) (160 mg, 0.52 mmol) in DCM (1.5 mL) was added 4 M HCl in dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo to give the title compound as a brownish solid (142 mg, 97%). 1 H NMR (400 MHz, CD 3 OD) δ 2.86 (s, 3H), 4.41-4.47 (m, 1H), 4.48-4.58 (m, 2H), 4.73-4.85 (m, 2H), 7.00-7.10 (m, 1H), 8.43-8.45 (m, 1H), 8.52 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=207.

Intermediate 27: 1-(5-Methylpyrimidin-2-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(5-methylpyrimidin-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate (649 mg, 3.11 mmol) in acetonitrile (10 mL) was added 2-chloro-5-methylpyrimidine (400 mg, 3.11 mmol) followed by N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). The mixture was heated in a microwave at 130° C. for 3 h. The solvent was removed, and the residue was purified on silica gel eluting with a 30%-100% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (373 mg, 45%). 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 2.17 (s, 3H), 3.92 (dd, J=8, 6 Hz, 2H), 4.34 (t, J=8 Hz, 2H), 4.43-4.58 (m, 1H), 8.21 (s, 2H); LC-MS (LC-ES) M+H=265.

B. 1-(5-Methylpyrimidin-2-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(5-methylpyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 27A) (170 mg, 0.64 mmol) in DCM (6 mL) was added 4 M HCl in dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature overnight and the solvent was removed in vacuo to give the title compound as a pale yellow solid (164 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.31 (s, 3H), 4.43 (m, 3H), 4.71 (m, 2H), 8.55 (m, 2H); LC-MS (LC-ES) M+H=165.

Intermediate 28: 4-(Azetidin-3-yloxy)benzo[d]thiazole hydrochloride

A. tert-Butyl 3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (1.47 g, 5.85 mmol) and benzo[d]thiazol-4-ol (0.884 g, 5.85 mmol) in DMF (40 mL) was added cesium carbonate (2.10 g, 6.43 mmol). The mixture was heated to 80° C. overnight, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 5%-70% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (1.35 g, 75%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.44 (s, 9H), 4.21 (dd, J=10, 4 Hz, 2H), 4.32-4.42 (m, 2H), 5.14-5.19 (m, 1H), 6.64 (d, J=8 Hz, 1H), 7.35 (t, J=8 Hz, 1H), 7.54-7.64 (m, 1H), 8.94 (s, 1H); LC-MS (LC-ES) M+H=307.

B. 4-(Azetidin-3-yloxy)benzo[d]thiazole hydrochloride

To tert-butyl 3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxylate (Intermediate 28A) (1.35 g, 4.41 mmol) in methanol (3 mL) was added 4 M HCL in dioxane (10 mL, 40 mmol). The mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo to give the title compound as a white solid (1.23 g, 100%). 1 H NMR (400 MHz, CD 3 OD) δ 4.32 (dd, J=12, 5 Hz, 2H), 4.65 (dd, J=12, 6 Hz, 2H), 5.42-5.50 (m, 1H), 6.98 (d, J=8 Hz, 1H), 7.49 (t, J=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 9.42 (s, 1H); LC-MS (LC-ES) M+H=207.

Alternatively, intermediate 28A can be converted to the trifluoroacetic acid salt

C. 4-(Azetidin-3-yloxy)benzo[d]thiazole hydrochloride trifluoroacetic acid salt

To tert-butyl 3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxylate (Intermediate 28A) (4.00 g, 12.4 mmol) in DCM (100 mL) at 0° C., TFA (16.0 mL, 208 mmol) was added. After 4 h, the solvent was removed in vacuo, and the residue triturated with diethyl ether (3×100 mL) to give the title compound as an off-white solid (3.70 g, 97%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 4.10-4.19 (m, 2H), 4.48-4.59 (m, 2H), 5.32-5.40 (m, 1H), 6.89-6.96 (m, 1H), 7.39-7.45 (m, 1H), 7.79-7.86 (m, 1H), 9.10 (br s, 2H), 9.35 (s, 1H); LC-MS (LC-ES) M+H=207.

Intermediate 29: 1-(5-Fluoropyrimidin-2-yl)piperidin-4-amine dihydrochloride

A. tert-Butyl (1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)carbamate

To tert-butyl piperidin-4-ylcarbamate (1.10 g, 5.50 mmol) in acetonitrile (12 mL), 2-chloro-5-fluoropyrimidine (0.66 g, 5.0 mmol) was added. The mixture was heated in a microwave at 125° C. for 3 h. The reaction was cooled, and the resulting precipitate was collected by filtration to give the title compound. The filtrate was concentrated, and the residue was purified on silica gel eluting with a 10%-60% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give additional title compound as a white solid (1.26 g, 85%, total yield). 1 H NMR (400 MHz, CDCl 3 ) δ 1.27-1.42 (m, 2H), 1.46 (s, 9H), 2.02 (d, J=12 Hz, 2H), 3.06 (t, J=12 Hz, 2H), 3.63-3.80 (m, 1H), 4.40-4.49 (m, 1H), 4.55 (d, J=14 Hz, 2H), 8.19 (s, 2H); LC-MS (LC-ES) M+H=297.

B. 1-(5-Fluoropyrimidin-2-yl)piperidin-4-amine dihydrochloride

To tert-butyl (1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)carbamate (Intermediate 29A) (1.26 g, 4.25 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (10 mL, 40 mmol). The mixture was stirred at room temperature for 3 h and the solvent was removed in vacuo to give the title compound as a pale yellow solid (1.11 g, 97%). 1 H NMR (400 MHz, CD 3 OD) δ 1.57-1.74 (m, 2H), 2.09-2.23 (m, 2H), 3.09-3.23 (m, 2H), 3.45-3.55 (m, 1H), 4.70-4.82 (m, 2H), 8.45-8.54 (m, 2H); LC-MS (LC-ES) M+H=197.

Intermediate 30: 4-Nitrophenyl (1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)carbamate

To 4-nitrophenyl chloroformate (214 mg, 1.06 mmol) in DCM (4 mL) at 0° C. was slowly added 1-(5-fluoropyrimidin-2-yl)piperidin-4-amine dihydrochloride (Intermediate 29) (220 mg, 0.82 mmol) in DCM (12 mL) and N,N-diisopropylethylamine (0.29 mL, 1.6 mmol). After one hour, the reaction was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed in vacuo to afford the title compound (290 mg, 98%) which was used without further purification. LC-MS (LC-ES) M+H=362.

Intermediate 31: 4-Nitrophenyl (1-(5-fluoropyridin-2-yl)azetidin-3-yl)carbamate

A. Benzyl (1-(5-fluoropyridin-2-yl)azetidin-3-yl)carbamate

In a reaction vial, allylpalladium chloride dimer (33 mg, 0.091 mmol), 2-(di(adamantan-1-yl)phosphino)-N,N-dimethylaniline (77 mg, 0.18 mmol) and toluene (20 mL) were stirred for 10 min. The mixture was first clear and then turned cloudy. Sodium tert-butoxide (877 mg, 9.12 mmol) was added, then 2-chloro-5-fluoropyridine (600 mg, 4.56 mmol) and benzyl azetidin-3-ylcarbamate (1.13 g, 5.47 mmol). The vial was sealed and heated to 110° C. overnight. The mixture was cooled, filtered through Celite® and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified on silica gel eluting with 10 to 65% EtOAc/hexanes to afford the title compound (230 mg, 17% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 3.83 (t, J=7 Hz, 2H), 4.27 (t, J=7 Hz, 2H), 4.57 (br s, 1H), 5.11 (s, 2H), 6.45 (d, J=8 Hz, 1H), 7.23-7.44 (m, 6H), 7.92 (br s, 1H); LC-MS (LC-ES) M+H=302.

B. 1-(5-Fluoropyridin-2-yl)azetidin-3-amine

Benzyl (1-(5-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 31A) (0.230 g, 0.76 mmol) and 20 wt % Pearlman's catalyst (54 mg, 0.08 mmol) were stirred in 1:1 methanol: EtOAc (40 mL) and purged with hydrogen via balloon (3×) before stirring under a hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (130 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 3.72-3.89 (m, 2H), 3.94-4.06 (m, 1H), 4.27 (t, J=8 Hz, 2H), 6.48 (d, J=8 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 7.95 (s, 1H); LC-MS (LC-ES) M+H=168.

C. 4-Nitrophenyl (1-(5-fluoropyridin-2-yl)azetidin-3-yl)carbamate

To 4-nitrophenyl chloroformate (152 mg, 0.754 mmol) in acetonitrile (3 mL) at 0° C. was slowly added 1-(5-fluoropyridin-2-yl)azetidin-3-amine (Intermediate 31B) (220 mg, 0.82 mmol) in DCM (12 mL). After one hour, sodium bicarbonate (97 mg, 1.2 mmol) was added, and the reaction was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed in vacuo, the residue dissolved in EtOAc and washed with water and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with 10 to 60% EtOAc/hexanes to afford the title compound (39 mg, 20% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.84-4.02 (m, 2H), 4.42 (t, J=8 Hz, 2H), 4.75 (d, J=6 Hz, 1H), 5.67 (d, J=6 Hz, 1H), 6.34 (d, J=6 Hz, 1H), 7.21-7.31 (m, 1H), 7.35 (d, J=9 Hz, 2H), 8.06 (br s, 1H), 8.28 (d, J=9 Hz, 1H); LC-MS (LC-ES) M+H=333.

Intermediate 32: (trans)-N-(Azetidin-3-yl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide hydrochloride

A. tert-Butyl 3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidine-1-carboxylate

To a DMF (4 mL) solution of (trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid (Intermediate 25) (400 mg, 1.61 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (276 mg, 1.61 mmol) and N,N-diisopropylethylamine (0.56 mL, 0.32 mmol) was added, dropwise, a 50% solution of T3P in ethyl acetate (2.04 g, 3.21 mmol). The reaction was stirred 30 min, quenched with water and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with 0 to 20% MeOH/DCM to afford the title compound (635 mg, 98% yield) as a foam. 1 H NMR (400 MHz, CD 3 OD) δ 1.44 (s, 9H), 2.49-2.64 (m, 2H), 2.69-2.82 (m, 2H), 3.11-3.29 (m, 1H), 3.82 (dd, J=8, 6 Hz, 2H), 4.23 (t, J=8 Hz, 2H), 4.57 (t, J=6 Hz, 1H), 5.16 (t, J=6 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 9.16 (s, 1H); LC-MS (LC-ES) M+H=404.

B. (trans)-N-(Azetidin-3-yl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide hydrochloride

To tert-butyl 3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidine-1-carboxylate (Intermediate 32A) (630 mg, 1.56 mmol) in DCM (2.5 mL) and methanol (2.5 mL), 4 M HCl in dioxane (5 mL, 20 mmol) was added. The mixture was stirred at room temperature for 3 h and the solvent was removed in vacuo to give the title compound as a hygroscopic foam (596 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.47-2.70 (m, 2H), 2.74-2.87 (m, 2H), 3.64-3.69 (m, 1H), 3.74-3.82 (m, 1H), 4.17-4.28 (m, 2H), 4.29-4.38 (m, 2H), 5.12-5.31 (m, 1H), 7.06-7.15 (m, 1H), 7.57-7.65 (m, 1H), 7.76-7.83 (m, 1H), 9.98 (br s, 1H); LC-MS (LC-ES) M+H=304.

Intermediate 33: 1-(2-Methylpyrimidin-4-yl)azetidin-3-amine

A. Benzyl (1-(2-methylpyrimidin-4-yl)azetidin-3-yl)carbamate

To benzyl azetidin-3-ylcarbamate (810 mg, 3.9 mmol) in acetonitrile (15 mL), 4-chloro-2-methylpyrimidine (420 mg, 3.3 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.5 mmol) were added. The mixture was heated in a microwave at 120° C. for 1.5 h. The reaction was concentrated, and the residue was purified on silica gel eluting with a 5%-20% MeOH in DCM gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (1.38 g, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.48 (s, 3H), 3.97-4.13 (m, 2H), 4.45 (t, J=8 Hz, 2H), 4.56-4.66 (m, 1H), 5.12 (s, 2H), 6.32 (d, J=6 Hz, 1H), 7.23-7.48 (m, 5H), 8.03 (d, J=6 Hz, 1H); LC-MS (LC-ES) M+H=299.

B. 1-(2-Methylpyrimidin-4-yl)azetidin-3-amine

Benzyl (1-(2-methylpyrimidin-4-yl)azetidin-3-yl)carbamate (Intermediate 33A) (1.2 g, 4.0 mmol) was dissolved in EtOH (30 mL) and EtOAc (30 mL), and 10 wt % palladium on carbon (0.43 g, 0.40 mmol) was added under nitrogen and purged with hydrogen via balloon (3×) before stirring at room temperature overnight under a hydrogen atmosphere. The reaction was filtered through a pad of Celite® and rinsed with EtOAc and methanol. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (505 mg, 76%). 1 H NMR (CD 3 OD) δ 2.49 (s, 3H), 4.11 (dd, J=11, 4 Hz, 2H), 4.19-4.31 (m, 1H), 4.49 (dd, J=10, 8 Hz, 2H), 6.38 (d, J=6 Hz, 1H), 8.10 (d, J=6 Hz, 1H); LC-MS (LC-ES) M+H=165.

Intermediate 34: Racemic 2-((trans)-5-Aminotetrahydro-2H-pyran-2-yl)propan-2-ol

A. Racemic N-Benzyl-6-(((tertbutyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-amine

Benzylamine (3.17 mL, 32.6 mmol) was added to a solution of 6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-one (4 g, 10.9 mmol) (see; Bioorganic and Medicinal Chemistry 14 (2006), 3953) in MeOH (30 mL). After 1 h, the mixture was cooled to −78° C. and LiBH 4 (5.97 mL, 11.9 mmol) was added. After 1 h, allowed to warm to ROOM TEMPERATURE slowly overnight. The mixture was partitioned between EtOAc and saturated NaHCO 3 and the aqueous layer was extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na 2 SO 4 , and concentrated. The residue was purified by silica gel chromatography eluting with a 0%-40% EtOAc/EtOH (3:1) in hexanes gradient to afford the title compound as a yellow oil (3.49 g, 70% yield) (mixture of cis and trans isomers). LC-MS (ES-MS) M+H=460.

B. Racemic 6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-amine

A Fisher-Porter bottle was flushed with N 2 and charged with N-benzyl-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-amine (Intermediate 34A) (3.9 g, 8.5 mmol) and EtOH (80 mL). Under a N 2 atmosphere, Pearlman's catalyst (1.49 g, 2.12 mmol) was added, and the vessel was evacuated and flushed with N 2 and stirred under 50 psi H2 over 4 days. The vessel was evacuated and flushed with N 2 and filtered through a pad of Celite®, washing with MeOH. The filtrate was concentrated to give the title compound as a clear thick oil (2.98 g, 94%). LC-MS (ES-MS) M+H=370.

C. Racemic tert-Butyl (6-(((tertbutyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate

To a solution of 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-amine (Intermediate 34B) (2.98 g, 8.06 mmol) and Et 3 N (1.69 mL, 12.1 mmol) in DCM (100 mL) at 0° C. was added Boc 2 O (2.15 mL, 9.27 mmol). The mixture was stirred at 0° C. for 1 h then at room temperature overnight. The reaction was diluted with DCM and washed with water and brine. The aqueous phases were back extracted with DCM, and the combined organics were dried over Na 2 SO 4 , filtered, and concentrated to give a thick oil. The residue was purified by silica gel chromatography eluting with a 0%-20% EtOAc-hexanes gradient to afford the title compound as a thick oil (2.4 g, 70% yield). LC-MS (ES-MS) M+H=470.

D. Racemic tert-Butyl (6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate

To a solution of tert-butyl (6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate (Intermediate 34C) (2.4 g, 5.1 mmol) in THF (60 mL) at 0° C., was added TBAF (10.2 mL, 10.2 mmol, 1 M in THF). The reaction was stirred at room temperature for 2 h, concentrated to ca. half volume under reduced pressure, and 15 mL of saturated NaHCO 3 was added. The mixture was extracted with EtOAc (2×). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to give an oil. The residue was purified by silica gel chromatography (0-20% EtOAc-hexanes gradient) to afford the title compound as a white solid (1.12 g, 94% yield). This material was used directly in the next step.

E. Racemic 5-((tert-Butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid

To a 0° C. solution of tert-butyl (6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (Intermediate 34D) (1.10 g, 4.76 mmol) in DCM (10 mL), acetonitrile (10 mL), and water (15 mL), was added sodium periodate (4.07 g, 19.0 mmol) and ruthenium(III) chloride (99 mg, 0.48 mmol). The mixture was vigorously stirred for 3 h, then diluted with EtOAc (50 mL) and filtered to remove solids. To the filtrate was added 10 mL of MeOH, and the mixture was filtered to remove solids. To the filtrate was added 20 mL of 10% aqueous NaHSO 3 solution which resulted in decolorization. The pH was adjusted to ca. 2 with addition of 20% aqueous NaHSO 4 and the layers were separated. The aqueous layer was extracted with EtOAc (3×) and the combined organics were dried over MgSO 4 and concentrated to give the title compound as a yellow foam (1.21 g, quantitative yield), which was used without further purification. LC-MS (ES-MS) M−H=244.

F. Racemic Methyl 5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate

A solution of diazomethane (900 mg, 21.4 mmol) in DCM (generated from N-methyl-N-nitrosourea (2.5 g) added to 30% aqueous NaOH (50 mL) and DCM (40 mL) on ice) was added slowly to a 0° C. solution of 5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (Intermediate 34E) (1.05 g, 4.28 mmol) in DCM (50 mL), and the reaction was stirred at 0° C. for 30 minutes. The bath was removed and the mixture flushed well with N 2 to remove excess diazomethane. To this was added CH 3 CO 2 H (2 drops) with stirring (to quench any remaining diazomethane), and the solution was washed with saturated NaHCO 3 . The mixture was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc-hexanes gradient) to afford the title compound as a white waxy solid (882 mg, 79% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 1.42 (s, 9H), 1.71-1.82 (m, 1H), 2.00-2.17 (m, 2H), 3.13 (br s, 1H), 3.66 (dd, J=12, 2 Hz, 1H), 3.76 (s, 3H), 3.86-4.04 (m, 1H), 4.17 (dd, J=11, 3 Hz, 1H), 4.35 (br s, 1H).

G. Racemic Methyl 5-aminotetrahydro-2H-pyran-2-carboxylate hydrochloride

To methyl 5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate (Intermediate 34F) (880 mg, 3.39 mmol) was added 1,4-dioxane (25 mL), followed by 4 M HCl in dioxane (8.48 mL, 33.9 mmol). The mixture was stirred at ROOM TEMPERATURE overnight. The reaction was concentrated to give the title compound as a white solid (670 mg, 101% yield). LC-MS (ES-MS) M+H=160.

H. Racemic (trans)-Methyl 5-(dibenzylamino)tetrahydro-2H-pyran-2-carboxylate

To a solution of methyl 5-aminotetrahydro-2H-pyran-2-carboxylate hydrochloride (Intermediate 34G) (670 mg, 3.42 mmol) in acetonitrile (25 mL), was added potassium carbonate (1.89 g, 13.7 mmol) and benzyl bromide (0.92 mL, 7.7 mmol), and the mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc-hexanes gradient) to afford the title compound as a clear oil (881 mg, 76% yield), which was assigned as the trans isomer by NMR. 1 H NMR (400 MHz, CDCl 3 ) δ 1.54-1.75 (m, 2H), 2.05-2.17 (m, 2H), 2.83 (tt, J=11, 4 Hz, 1H), 3.42 (t, J=11 Hz, 1H), 3.58-3.74 (m, 7H), 3.86 (dd, J=12, 2 Hz, 1H), 4.09-4.17 (m, 1H), 7.11-7.48 (m, 10H); LC-MS (ES-MS) M+H=340.

I. Racemic 2-((trans)-5-(Dibenzylamino)tetrahydro-2H-pyran-2-yl)propan-2-ol

To a solution of (trans)-methyl 5-(dibenzylamino)tetrahydro-2H-pyran-2-carboxylate (Intermediate 34H) (535 mg, 1.58 mmol) in THF (18 mL) at 0° C. was added methylmagnesium bromide (4.20 mL, 12.6 mmol, 3 M in THF) dropwise. The mixture was allowed to warm to room temperature overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 1 M NH 4 Cl (25 mL). The mixture was extracted with EtOAc (2×), and the combined organics were dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-45%, EtOAc-hexanes gradient) to afford the title compound as a clear oil (268 mg, 50% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 1.07 (s, 3H), 1.13 (s, 3H), 1.22-1.38 (m, 1H), 1.58 (dd, J=12, 4 Hz, 1H), 1.71 (d, J=13 Hz, 1H), 2.03-2.12 (m, 1H), 2.39 (s, 1H), 2.72 (tt, J=11, 4 Hz, 1H), 2.99 (dd, J=11, 2 Hz, 1H), 3.40 (t, J=11 Hz, 1H), 3.58-3.73 (m, 4H), 3.99-4.09 (m, 1H), 7.06-7.50 (m, 10H); LC-MS (ES-MS) M+H=340.

J. Racemic 2-((trans)-5-Aminotetrahydro-2H-pyran-2-yl)propan-2-ol

To 2-((trans)-5-(d ibenzylamino)tetrahydro-2H-pyran-2-yl)propan-2-ol (Intermediate 341) (770 mg, 2.01 mmol) and EtOH (15 mL) under a N 2 atmosphere was added 20% palladium hydroxide (141 mg, 0.201 mmol), and the vessel was evacuated and flushed with N 2 and then stirred under 40 psi H 2 for 24 h. The vessel was evacuated and flushed with N 2 and the mixture filtered through a pad of Celite® and rinsed with EtOH and EtOAc. The filtrate was concentrated to give the title compound as a clear oil (310 mg, 97% yield). 1 H NMR (400 MHz, CD 3 OD) δ 1.16 (s, 3H), 1.18 (s, 3H), 1.26-1.38 (m, 1H), 1.39-1.52 (m, 1H), 1.75-1.84 (m, 1H), 2.09 (dt, J=12, 3 Hz, 1H), 2.69-2.76 (m, 1H), 3.01-3.13 (m, 2H), 3.95-4.04 (m, 1H); LC-MS (ES-MS) M+H=160.

Intermediate 35: 2-(3-Aminoazetidin-1-yl)isonicotinonitrile

A. Benzyl (1-(4-cyanopyridin-2-yl)azetidin-3-yl)carbamate

To benzyl azetidin-3-ylcarbamate hydrochloride (400 mg, 1.65 mmol) in acetonitrile (10 mL), 2-chloroisonicotinonitrile (274 mg, 1.98 mmol) and N,N-diisopropylethylamine (0.72 mL, 4.1 mmol) were added. The mixture was heated in a microwave at 135° C. for 2.5 h. The reaction was concentrated, and the residue was purified on silica gel eluting with a 20%-90% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (185 mg, 34%). 1 H NMR (400 MHz, CD 3 OD) δ 3.91 (dd, J=8, 6 Hz, 2H), 4.34 (t, J=8 Hz, 2H), 4.56-4.64 (m, 1H), 5.09 (s, 2H), 6.72 (s, 1H), 6.84 (d, J=5 Hz, 1H), 7.17-7.45 (m, 5H), 8.17 (d, J=5 Hz, 1H); LC-MS (LC-ES) M+H=309.

B. 2-(3-Aminoazetidin-1-yl)isonicotinonitrile

Benzyl (1-(4-cyanopyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 35A) (185 mg, 0.60 mmol) was dissolved in MeOH (5 mL) and EtOAc (5 mL), and 10 wt % palladium on carbon (128 mg, 0.12 mmol) was added under nitrogen. The reaction was purged with hydrogen via balloon (3×) before stirring under a hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated and the residue was purified on silica gel eluting with a 20%-90% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (55 mg, 53%). 1 H NMR (CDCl 3 ) δ 3.61-3.78 (m, 2H), 3.92-4.08 (m, 1H), 4.20-4.41 (m, 2H), 6.44 (s, 1H), 6.72 (d, J=5 Hz, 1H), 8.22 (d, J=5 Hz, 1H); LC-MS (LC-ES) M+H=175.

Intermediate 36: 4-Nitrophenyl ((trans)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate

To 4-nitrophenyl chloroformate (122 mg, 0.604 mmol) in acetonitrile (2 mL) at 0° C. was slowly added 2-((trans)-5-aminotetrahydro-2H-pyran-2-yl)propan-2-ol (Intermediate 34) (74 mg, 0.47 mmol) in acetonitrile (2 mL). After 30 min, sodium bicarbonate (78 mg, 0.93 mmol) was added, and the mixture was allowed to warm to room temperature. After 1 h, the solvent was removed in vacuo, and the residue was purified on silica gel, eluting with a 0%-60% EtOAc in hexanes gradient to give the title compound as a white solid (78 mg, 52%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.19 (s, 3H), 1.23 (s, 3H), 1.38-1.66 (m, 2H), 1.81 (d, J=12 Hz, 1H), 2.27 (d, J=12 Hz, 1H), 2.42 (br s, 1H), 3.03-3.26 (m, 2H), 3.64-3.87 (m, 1H), 4.26 (dd, J=11, 3 Hz, 1H), 4.89 (d, J=8 Hz, 1H), 7.34 (d, J=9 Hz, 2H), 8.27 (d, J=9 Hz, 2H); LC-MS (LC-ES) M+H=325.

Intermediate 37: 1-(Pyridin-2-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate

To tert-butyl azetidin-3-ylcarbamate hydrochloride (500 mg, 2.40 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.84 mL, 4.8 mmol) followed by 2-fluoropyridine (233 mg, 2.40 mmol). The mixture was heated at 85° C. for overnight, cooled, diluted with EtOAc, washed with water, and the aqueous extracted with EtOAc. The combined organic layers were washed with water (2×) and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 20%-70% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (90 mg, 15%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.49 (s, 9H), 3.82 (dd, J=8, 5 Hz, 2H), 4.38 (t, J=8 Hz, 2H), 4.66 (s br, 1H), 6.33 (d, J=8 Hz, 1H), 6.61-6.70 (m, 1H), 7.42-7.53 (m, 1H), 8.18 (d, J=4 Hz, 1H); LC-MS (LC-ES) M+H=250.

B. 1-(Pyridin-2-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 37A) (90 mg, 0.36 mmol) in DCM (1 mL), 4 M HCl in dioxane (2 mL, 8 mmol) was added. The mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo to give the title compound as a white solid (84 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.38-4.50 (m, 3H), 4.69-4.78 (m, 2H), 7.01 (d, J=9 Hz, 1H), 7.03-7.09 (m, 1H), 8.00 (d, J=6 Hz, 1H), 8.05-8.12 (m, 1H); LC-MS (LC-ES) M+H=150.

Intermediate 38: 2-(2-Aminothiazol-4-yl)propan-2-ol trifluoroacetic acid salt

A. tert-Butyl (4-(2-hydroxypropan-2-yl)thiazol-2-yl)carbamate

To a solution of methyl 2-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (0.50 g, 1.9 mmol) in THF (13 mL) at 0° C. was added methylmagnesium bromide (2.58 mL, 7.7 mmol, 3 M in THF) dropwise. The mixture was allowed to warm to room temperature and stirred 36 h. The mixture was quenched with water, extracted with EtOAc (2×), and the combined organics were dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (30-75% EtOAc-hexanes gradient) to afford the title compound as a white solid (360 mg, 72% yield). 1 H NMR (400 MHz, CD 3 OD) δ 1.50 (s, 6H), 1.54 (s, 9H), 6.78 (s, 1H); LC-MS (ES-MS) M+H=259.

B. 2-(2-Aminothiazol-4-yl)propan-2-ol trifluoroacetic acid salt

To a stirred solution of tert-butyl (4-(2-hydroxypropan-2-yl)thiazol-2-yl)carbamate (Intermediate 38A) (700 mg, 2.71 mmol) in MeOH (2.5 mL) was added trifluoroacetic acid (2.5 mL, 32.4 mmol). The resulting mixture was stirred at room temperature for 1 h. Removing the solvent in vacuo afforded the title compound (720 mg, 98%). 1 H NMR (400 MHz, CD 3 OD) δ 1.53 (s, 6H), 3.98 (s, 1H), 6.60 (s, 1H); LC-MS (LC-ES) M+H—H 2 O=141.

Intermediate 39: (trans)-4-(2-Methoxyethoxy)cyclohexanamine

A. trans-4-(Dibenzylamino)cyclohexanol

Benzyl bromide (60 g, 350 mmol) was added to (trans)-4-aminocyclohexanol hydrochloride (20 g, 174 mmol) and sodium bicarbonate (40 g, 476 mmol) in EtOH (400 mL) at room temperature. The reaction was heated to reflux for 36 h, filtered and concentrated to give a solid. The solid was taken up in hexanes. The reaction was stirred overnight, filtered and air dried to afford the title compound (33.2 g, 65%). 1 H NMR (CDCl 3 ) δ 1.14-1.28 (m, 2H), 1.30 (d, J=5 Hz, 1H), 1.38-1.52 (m, 2H), 1.91 (d, J=12 Hz, 2H), 2.00 (br s, 1H), 2.53 (tt, J=12, 3 Hz, 1H), 3.50-3.59 (m, 1H), 3.62 (s, 4H), 7.18-7.25 (m, 2H), 7.27-7.32 (m, 4H), 7.33-7.38 (m, 4H).

B. (trans)-N,N-Dibenzyl-4-(2-methoxyethoxy)cyclohexanamine hydrochloride

A saturated solution of KOH (175 g) and water (100 g) was prepared and allowed to cool to ambient temperature. A 250 mL three neck round bottom flask equipped with overhead stirrer was charged with (trans)-4-(dibenzylamino)cyclohexanol (Intermediate 39A) (10 g, 33.9 mmol), 1,4-dioxane (10 mL) and 1-bromo-2-methoxyethane (10 g, 71.9 mmol). To the stirred solution was added Aliquot 336 (1 g, ca. 2.25 mmol) followed by a portion of the saturated KOH solution (70 mL). The reaction mixture was stirred at ca. 42° C. internal temp under N 2 atmosphere for 4 h and 40 min at which point HPLC showed 77% conversion. Additional solid KOH (5 g) and 1-bromo-2-methoxyethane (10 g) were added, and stirring was continued overnight. The reaction mixture was cooled to ambient temp, and TBME (100 mL), water (50 mL) and brine (50 mL) were added. The aqueous phase was extracted with TBME (75 mL) and the combined TBME layers were washed with brine, dried over MgSO 4 , filtered and the TBME filtrate was stirred at room temperature, and 4 N HCl in dioxane (10 mL) was added dropwise with rapid stirring. The slurry was stirred at room temperature for 20 min and the solids were collected by filtration washing with TBME to give the title compound as an off-white solid (13.1 g, 94%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.89-1.02 (m, 2H), 1.63-1.75 (m, 2H), 2.07 (d, J=11 Hz, 2H), 2.27 (d, J=11 Hz, 2H), 2.48-2.53 (m, 1H), 2.96-3.06 (m, 1H), 3.22 (s, 3H), 3.35-3.41 (m, 2H), 3.47-3.51 (m, 2H), 4.12 (dd, J=13, 5 Hz, 2H), 4.43 (dd, J=13, 5 Hz, 2H), 7.37-7.44 (m, 6H), 7.61-7.68 (m, 4H), 10.97 (br s, 1H).

C. (trans)-4-(2-Methoxyethoxy)cyclohexanamine

(trans)-N,N-Dibenzyl-4-(2-methoxyethoxy)cyclohexanamine hydrochloride (Intermediate 39B) (19.7 g, 50.5 mmol) in water (150 mL) was stirred until near solution was achieved. TBME (150 mL) was added, then 1 N NaOH (50 mL) was added slowly over 5 minutes (internal temp stayed steady at ambient without external cooling). The layers were separated, and the aqueous phase was extracted with TBME (30 mL). The combined TBME layers were washed with brine, dried over MgSO 4 , filtered and concentrated chasing with EtOH. The resulting light amber oil was dissolved in EtOH (150 mL), and purged with N 2 . Pd(OH) 2 on activated charcoal (1.6 g, 10-20% Pd; ˜50% water as stabilizer) was added, and the stirred mixture was evacuated and purged with N 2 and then with Hz, and stirred under H 2 atmosphere at room temperature, monitoring uptake with a Buchi Pressflow apparatus. After 3 h of rapid stirring, the reaction appeared to be slowing down, so the reaction vessel was evacuated and purged with N 2 , and charged with an additional amount of Pd(OH) 2 (1.62 g), and hydrogenolysis was continued for an additional 80 min. The vessel was evacuated and purged with N 2 , and the reaction mixture was filtered through a millipore filter pad containing Celite®. The filtrate was concentrated to afford the title compound as a nearly colorless oil (7.6 g, 87%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.94-1.18 (m, 4H), 1.68-1.76 (m, 2H), 1.85-1.93 (m, 2H), 2.46-2.55 (m, 1H), 3.11-3.20 (m, 1H), 3.23 (s, 3H), 3.37-3.42 (m, 2H), 3.47-3.51 (m, 2H).

Intermediate 40: (trans)-N-((trans)-3-Aminocyclobutyl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide hydrochloride

To tert-butyl ((trans)-3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)cyclobutyl)carbamate (Example 66) (185 mg, 0.44 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (4 mL, 16 mmol). The mixture was stirred at room temperature for 30 min, and the solvent was removed in vacuo to give the title compound as a white solid (194 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.41-2.59 (m, 6H), 2.72-2.83 (m, 2H), 3.14-3.27 (m, 1H), 3.79-4.00 (m, 1H), 4.40-4.64 (m, 1H), 5.15-5.24 (m, 1H), 7.00-7.04 (m, 1H), 7.53-7.59 (m, 1H), 7.72-7.77 (m, 1H), 9.70 (s, 1H); LC-MS (LC-ES) M+H=318.

Intermediate 41: 1-(Pyridin-2-yl)azetidin-3-amine

A. Benzyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate

To a reaction vial with benzyl azetidin-3-ylcarbamate hydrochloride (800 mg, 3.30 mmol) in DMF (3 mL) was added 2-fluoropyrimidine (320 mg, 3.30 mmol) and N,N-diisopropylethylamine (1.15 mL, 6.59 mmol). The mixture was heated at 85° C. overnight, cooled, diluted with EtOAc and washed (2×) with water. The aqueous layers were extracted with EtOAc, the combined organic layers washed with water (3×) and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 20%-70% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (160 mg, 17%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.81-3.89 (m, 2H), 4.31-4.41 (m, 2H), 4.69 (br s, 1H), 5.13 (s, 2H), 5.24 (br s, 1H), 6.31 (d, J=8 Hz, 1H), 6.59-6.70 (m, 1H), 7.30-7.42 (m, 5H), 7.44-7.55 (m, 1H), 8.15 (d, J=4 Hz, 1H); LC-MS (LC-ES) M+H=284.

B. 1-(Pyridin-2-yl)azetidin-3-amine

Palladium on carbon (135 mg, 0.13 mmol) was added to benzyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 41A) (0.180 g, 0.64 mmol) in EtOH (10 mL) at 25° C. under a nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred overnight under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (89 mg, 94% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 3.59-3.74 (m, 2H), 3.90-4.06 (m, 1H), 4.16-4.40 (m, 2H), 6.24-6.32 (m, 1H), 6.55-6.64 (m, 1H), 7.41-7.49 (m, 1H), 8.15 (d, J=4 Hz, 1H); LC-MS (LC-ES) M+H=150.

Intermediate 42: Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(pyrrolidin-3-yl)cyclobutanecarboxamide hydrochloride

A. Racemic 3-((trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)pyrrolidine-1-carboxylate

(trans)-3-(Benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid (Intermediate 25) (350 mg, 0.80 mmol), was dissolved in DMF (8 mL) followed by the addition of N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) and HATU (578 mg, 1.52 mmol). The reaction was stirred at room temperature for ca. 5 min, and tert-butyl 3-aminoazetidine-1-carboxylate (262 mg, 1.52 mmol) was added. After 2 h, the reaction was quenched with water and MeOH, and loaded onto a semi-prep HPLC (NH 4 OH as modifier) to afford the title compound as a tan solid (71 mg, 21% yield). LC-MS (LC-ES) peak at T=0.84 min; M+H=418.

B. Racemic (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(pyrrolidin-3-yl)cyclobutanecarboxamide hydrochloride

To 3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)pyrrolidine-1-carboxylate (Intermediate 42A) (76 mg, 0.18 mmol) in DCM (1 mL) was added 4 N HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give the title compound as a pale yellow solid (70 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.31-2.42 (m, 1H), 2.55-2.70 (m, 1H), 2.74-2.89 (m, 2H), 3.04-3.11 (m, 2H), 3.45-3.59 (m, 2H), 3.59-3.71 (m, 1H), 3.73-3.88 (m, 2H), 3.90-3.97 (m, 1H), 4.74 (br s, 1H), 5.47 (t, J=6 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.80-7.88 (m, 1H), 8.04 (d, J=8 Hz, 1H), 10.16 (br s, 1H); LC-MS (LC-ES) M+H=318.

Intermediate 43: Racemic 2-(6-Aminospiro[3.3]heptan-2-yl)propan-2-ol

A. Methyl 3-methylenecyclobutanecarboxylate

To a DMF (350 mL) mixture of 3-methylenecyclobutanecarboxylic acid (11.6 g, 103 mmol) and cesium carbonate (70.8 g, 217 mmol) was added iodomethane (17.6 g, 124 mmol). After stirring overnight, the reaction was partitioned between Et 2 O and water, the organic layer separated and the aqueous layer extracted with Et 2 O (3×). The combined organic layers were washed with water, dried over MgSO 4 , filtered and concentrated to give the title compound (10.9 g, 84%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 2.85-2.92 (m, 2H), 2.92-3.04 (m, 2H), 3.09-3.17 (m, 1H), 3.70 (s, 3H), 4.77-4.82 (m, 2H).

B. Methyl 6-oxospiro[3.3]heptane-2-carboxylate

To a methyl acetate (45 mL) solution of methyl 3-methylenecyclobutanecarboxylate (Intermediate 43A) was added copper powder (2.77 g, 43.6 mmol) and zinc powder (5.70 g, 87 mmol). To this mixture was added a methyl acetate (45 mL) solution of 2,2,2-trichloroacetyl chloride (4.86 mL, 43.6 mmol) and phosphorus oxychloride (0.37 mL, 4.0 mmol) dropwise over 2 h. After 3 h, the reaction was cooled to 0° C., and additional zinc powder (5.70 g, 87 mmol) was added, followed by acetic acid (22.7 mL, 400 mmol) dropwise at a rate keeping the temperature below 7° C. The reaction was allowed to slowly warm to room temperature and after stirring overnight was filtered through Celite®, rinsing with EtOAc. The filtrate was carefully washed (warning: gas evolution) with saturated aqueous NaHCO 3 (2×200 mL), and the aqueous layers extracted with 1:1 EtOAc:Et 2 O (2×100 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated, and the residue purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (4.10 g, 61%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 2.38-2.48 (m, 2H), 2.50-2.61 (m, 2H), 3.00-3.09 (m, 2H), 3.09-3.22 (m, 3H), 3.68 (s, 3H).

C. Racemic Methyl 6-(dibenzylamino)spiro[3.3]heptane-2-carboxylate

To a THF (200 mL) solution of methyl 6-oxospiro[3.3]heptane-2-carboxylate (Intermediate 43B) (3.89 g, 23.1 mmol) was added dibenzylamine (4.67 mL, 24.29 mmol). After 10 min, the reaction was cooled to 0° C., and sodium triacetoxyborohydride (7.35 g, 34.7 mmol) was added as a solid, portionwise, over 10 minutes followed by 4-5 drops of glacial acetic acid. The reaction was allowed to warm to room temperature. After 4 h, the reaction mixture was diluted with water (20 mL), extracted with Et 2 O (200 mL) and washed with saturated sodium bicarbonate (100 mL). The aqueous layer was extracted with Et 2 O (1×100 mL) and the organic layers were combined, dried over MgSO 4 , filtered and concentrated, and the residue was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (5.00 g, 62%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.74-1.92 (m, 2H), 1.97-2.34 (m, 6H), 2.90-3.09 (m, 2H), 3.35-3.51 (m, 4H), 3.64 (s, 3H), 7.09-7.44 (m, 10H); LC-MS (LC-ES) M+H=350.

D. Racemic 2-(6-(Dibenzylamino)spiro[3.3]heptan-2-yl)propan-2-ol

To methyl 6-(dibenzylamino)spiro[3.3]heptane-2-carboxylate (Intermediate 43C) (5.00 g, 14.3 mmol) in Et 2 O (200 mL) at 0° C. was added a 3.0 M solution of methylmagnesium chloride in diethyl ether (15.7 mL, 47.2 mmol). After 30 minutes, the mixture was warmed to room temperature for 70 min, cooled to 0° C., quenched with 3 N HCl and partitioned between saturated aqueous NaHCO 3 (150 mL) and Et 2 O (100 mL). The aqueous layer was separated and extracted with ethyl acetate 100 mL). The organic layers were combined, dried over MgSO 4 , filtered and concentrated, and the residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (4.65 g, 93%) as a white solid. 1 H NMR (CDCl 3 ) δ 1.06 (s, 6H), 1.66-1.97 (m, 7H), 2.05-2.31 (m, 2H), 2.91-3.06 (m, 1H), 3.45 (s, 4H), 7.09-7.41 (m, 10H); LC-MS (LC-ES) M+H=350.

E. Racemic 2-(6-Aminospiro[3.3]heptan-2-yl)propan-2-ol

To 2-(6-(dibenzylamino)spiro[3.3]heptan-2-yl)propan-2-ol (Intermediate 43D) (4.10 g, 11.7 mmol) and EtOH (100 mL) under an N 2 atmosphere was added 20% palladium hydroxide (329 mg, 2.35 mmol), and the vessel was evacuated and flushed with N 2 and then stirred under 35 psi H2 overnight. The vessel was evacuated and flushed with N 2 and the mixture filtered through a pad of Celite® and rinsed with MeOH. The filtrate was concentrated to give the title compound as a white solid (2.18 g, quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ 1.07 (d, J=1 Hz, 6H), 1.39 (s, 3H), 1.52-1.61 (m, 1H), 1.63-1.69 (m, 1H), 1.74-1.97 (m, 4H), 2.11-2.27 (m, 2H), 2.35-2.48 (m, 1H), 3.30 (quin, J=8 Hz, 1H).

Intermediate 44: Racemic 4-Nitrophenyl (1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)carbamate

A. Racemic tert-Butyl (1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)carbamate

1,1,1-Trifluoropropan-2-yl trifluoromethanesulfonate (0.472 g, 1.92 mmol) was suspended in 1,4-dioxane (3.0 ml), then tert-butyl piperidin-4-ylcarbamate (0.30 g, 1.5 mmol) and N,N-diisopropylethylamine (0.55 ml, 3.2 mmol) were added. The reaction was heated to 90° C. for 24 hours, cooled, diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel eluting with 20 to 50% EtOAc in heptanes to afford the title compound (243 mg, 55% yield). 1 H NMR (400 MHz, CD 3 OD) δ 1.23 (d, J=7 Hz, 3H), 1.36-1.52 (m, 11H), 1.83 (t, J=8 Hz, 2H), 2.50 (t, J=11 Hz, 1H), 2.61 (t, J=11 Hz, 1H), 2.92 (t, J=11 Hz, 2H), 3.26-3.36 (m, 2H); LC-MS (LC-ES) M+H=297.

B. Racemic 1-(1,1,1-Trifluoropropan-2-yl)piperidin-4-amine dihydrochloride

To tert-butyl (1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)carbamate (Intermediate 44A) (240 mg, 0.81 mmol) in 1,4-dioxane (1 mL) was added 4 N HCl in dioxane (1 mL, 4 mmol). The mixture was stirred at room temperature for 3 h, and the solvent was removed in vacuo to give the title compound as a white solid (235 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.22 (d, J=7 Hz, 3H), 1.29-1.42 (m, 2H), 1.51-1.67 (m, 2H), 1.87-1.96 (m, 2H), 2.94-3.10 (m, 2H) 3.34-3.49 (m, 1H), 3.57-3.75 (m, 1H); LC-MS (LC-ES) M+H=197.

C. Racemic 4-Nitrophenyl (1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)carbamate

To 4-nitrophenyl chloroformate (115 mg, 0.571 mmol) in DCM (1 mL) at 0° C. was slowly added 1-(1,1,1-trifluoropropan-2-yl)piperidin-4-amine dihydrochloride (Intermediate 44B) (100 mg, 0.372 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in DCM (2 mL). The reaction was allowed to slowly warm to room temperature overnight. The solvent was removed in vacuo, and the residue was purified on silica gel eluting with 5 to 50% EtOAc/Hex to afford the title compound (23 mg, 17% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.16 (d, J=7 Hz, 3H), 1.38-1.52 (m, 2H), 1.77-1.86 (m, 2H), 2.39-2.50 (m, 2H), 2.88 (t, J=13 Hz, 2H), 3.29-3.39 (m, 1H), 3.40-3.52 (m, 1H), 7.41 (d, J=9 Hz, 2H), 8.23-8.31 (m, 2H); LC-MS (LC-ES) M+H=362.

Intermediate 45: Benzyl 4-(((4-nitrophenoxy)carbonyl)amino)piperidine-1-carboxylate

To 4-nitrophenyl chloroformate (260 mg, 1.29 mmol) in DCM (2 mL) at 0° C. was slowly added benzyl 4-aminopiperidine-1-carboxylate (200 mg, 0.854 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.86 mmol) in DCM (4 mL). The reaction was allowed to slowly warm to room temperature. After 5 h, the solvent was removed in vacuo, and the residue was purified on silica gel eluting with a 0% to 50% EtOAc in hexanes gradient to afford the title compound (307 mg, 90% yield) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.33-1.46 (m, 2H) 1.82-1.92 (m, 2H) 2.99 (br s, 2H) 3.62 (br s, 1H) 3.91-4.01 (m, 2H) 5.09 (s, 2H) 7.28-7.47 (m, 6H) 8.12 (d, J=8 Hz, 1H) 8.24-8.31 (m, 2H); LC-MS (LC-ES) M+H=400.

Intermediate 46: 4-Nitrophenyl (1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamate

A. tert-Butyl (1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamate

N,N-Diisopropylethylamine (0.64 mL, 3.7 mmol) was added to tert-butyl piperidin-4-ylcarbamate (368 mg, 1.84 mmol) in 1,4-dioxane (3.0 mL) at room temperature, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (512 mg, 2.20 mmol), and the reaction was stirred at 75° C. for 7 days. The mixture was concentrated, and the residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:4) to give the title compound (501 g, 92% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.36 (s, 9H), 1.37 (dq, J=12, 4 Hz, 2H), 1.64 (br d, J=11 Hz, 2H), 2.30 (dt, J=11, 2 Hz, 2H), 2.83 (br d, J=12 Hz, 2H), 3.09 (q, J=10 Hz, 2H), 3.12-3.26 (m, 1H), 6.76 (d, J=8 Hz, 1H); LC-MS (LC-ES) M+H=283.

B. 1-(2,2,2-Trifluoroethyl)piperidin-4-amine dihydrochloride

4.0 M Hydrochloric acid (4.44 mL, 17.8 mmol) in dioxane was added to tert-butyl (1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamate (Intermediate 46A) (0.501 g, 1.78 mmol) in MeOH (4.4 mL) at room temperature, and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated to give the title compound (0.460 g, 97% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.56 (br q, J=11 Hz, 2H), 1.85 (br d, J=11 Hz, 2H), 2.38-2.56 (m, 2H), 2.90-3.08 (m, 3H), 3.28 (br s, 2H), 4.95 (br s, 1H), 8.00 (br s, 3H); LC-MS (LC-ES) M+H=183.

C. 4-Nitrophenyl (1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamate

To 4-nitrophenyl chloroformate (240 mg, 1.19 mmol) in DCM (2 mL) at 0° C. was slowly added 1-(2,2,2-trifluoroethyl)piperidin-4-amine dihydrochloride (Intermediate 46B) (200 mg, 0.78 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol) in DCM (4 mL). The reaction was allowed to slowly warm to room temperature overnight. The resulting mixture contained solid material which was collected by vacuum filtration and dried to afford the title compound (87 mg, 32%) as a white solid. The filtrate was evaporated in vacuo, and the residue was purified on silica gel eluting with a 5% to 50% EtOAc in hexanes gradient to afford additional title compound (115 mg, 42% yield) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.44-1.63 (m, 2H), 1.81 (d, J=14 Hz, 2H), 2.42 (t, J=11 Hz, 2H), 2.91 (d, J=12 Hz, 2H), 3.08-3.22 (m, 2H), 3.33-3.43 (m 1H), 7.41 (d, J=9 Hz, 2H), 7.99-8.13 (m, 1H), 8.27 (d, J=9 Hz, 2H); LC-MS (LC-ES), M+H=348.

Intermediate 47: 4-Nitrophenyl 3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxylate

To 4-nitrophenyl chloroformate (390 mg, 1.94 mmol) in DCM (5 mL) at 0° C. was slowly added 4-(azetidin-3-yloxy)benzo[d]thiazole hydrochloride (Intermediate 28) (300 mg, 1.24 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.9 mmol) in DCM (10 mL). The reaction was allowed to slowly warm to room temperature overnight. The solvent was removed in vacuo, and the residue was purified on silica gel eluting with a 0%-50% EtOAc in hexanes gradient to afford the title compound (331 mg, 72% yield) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 4.07-4.18 (m, 1H), 4.29-4.36 (m, 1H), 4.52-4.61 (m, 1H), 4.70-4.79 (m, 1H), 5.32-5.40 (m, 1H), 6.91 (d, J=12 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 7.48 (d, J=12 Hz, 2H), 7.78 (d, J=12 Hz, 1H), 8.29 (d, J=12 Hz, 2H), 9.32 (s, 1H); LC-MS (LC-ES), M+H=372.

Intermediate 48: Racemic 1-(3-Aminopiperidin-1-yl)ethanone hydrochloride

A. Racemic tert-Butyl (1-acetylpiperidin-3-yl)carbamate

To a solution of 3-((tert-butoxycarbonyl)amino)piperidine (400 mg, 2.0 mmol) in DCM (10 mL) was added triethylamine (0.50 mL, 3.6 mmol) followed by acetyl chloride (0.20 mL, 2.8 mmol). After stirring overnight, the reaction was concentrated, diluted with EtOAc and washed with 0.5 N aqueous HCl, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow solid (330 mg, 68% yield). NMR showed a mixture of rotamers. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.20-1.34 (m, 2H), 1.38 (s, 4.5H), 1.40 (s, 4.5H), 1.62-1.71 (m, 1H), 1.73-1.82 (m, 1H), 1.94 (s, 1.5H), 1.97 (s, 1.5H), 2.87-2.96 (m, 1H), 3.01-3.08 (m, 1H), 3.52-3.63 (m, 1H), 3.67-3.74 (m, 1H), 4.13-4.17 (m, 0.5H), 4.17-4.22 (m, 0.5H), 6.84 (d, J=12 Hz, 0.5H), 6.96 (m, J=12 Hz, 0.5H).

B. Racemic 1-(3-Aminopiperidin-1-yl)ethanone hydrochloride

To tert-butyl (1-acetylpiperidin-3-yl)carbamate (Intermediate 48A) (170 mg, 0.70 mmol) in methanol (0.5 mL) was added 4 N HCl in dioxane (1 mL, 4 mmol). The mixture was stirred at room temperature for 1.5 h, and the solvent was removed in vacuo. The resulting residue was triturated with Et 2 O to give the title compound as a beige solid (115 mg, 92%). NMR showed a mixture of rotamers. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.35-1.64 (m, 2H), 1.70-1.77 (m, 1H), 1.91-1.99 (m, 1H), 2.01 (s, 3H), 2.93-3.28 (m, 3H), 3.67-3.83 (m, 1H), 4.10-4.13 (m, 0.5H), 4.14-4.17 (m, 0.5H), 8.06 (br s, 1H), 8.17 (br s, 1H).

Intermediate 49: Racemic Methyl 3-aminopiperidine-1-carboxylate hydrochloride

A. Racemic Methyl 3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate

To a solution of 3-((tert-butoxycarbonyl)amino)piperidine (400 mg, 2.0 mmol) in DCM (10 mL) was added triethylamine (0.50 mL, 3.6 mmol) followed by methyl chloroformate (0.20 mL, 2.6 mmol). After stirring overnight, the reaction was concentrated, diluted with EtOAc and washed with 0.5 N HCl water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound as a white solid (502 mg, 97% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.27-1.35 (m, 2H), 1.38 (s, 9H), 1.62-1.69 (m, 1H), 1.72-1.80 (m, 1H), 2.74-2.83 (m, 1H), 3.20-3.28 (m, 1H), 3.52-3.58 (m, 1H), 3.58 (s, 3H), 3.66-3.74 (m, 1H), 3.76-3.89 (m, 1H), 6.85-6.91 (m, 1H).

B. Methyl 3-aminopiperidine-1-carboxylate hydrochloride

To methyl 3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (Intermediate 49A) (100 mg, 0.39 mmol) in methanol (0.5 mL) was added 4 N HCl in dioxane (1 mL, 4 mmol). The mixture was stirred at room temperature for 1.5 h, and the solvent was removed in vacuo. The resulting residue was triturated with Et 2 O to give the title compound as a white solid (81 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.36-1.59 (m, 2H), 1.64-1.74 (m, 1H), 1.89-1.96 (m, 1H), 2.95-3.19 (m, 3H), 3.56-3.65 (m, 4H), 3.87-3.96 (m, 1H), 8.07 (br s, 2H).

Intermediate 50: Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-(morpholin-2-ylmethyl)azetidine-1-carboxamide

A. Racemic tert-Butyl 2-((3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)methyl)morpholine-4-carboxylate

To tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (370 mg, 1.71 mmol) in NMP (4 mL) was added 4-nitrophenyl 3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxylate (Intermediate 47) (250 mg, 0.67 mmol). The reaction was heated to 80° C. overnight, poured into saturated aqueous NaHCO 3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, concentrated and the residue purified on silica gel, eluting with a 0%-75% EtOAc-EtOH (3:1) in hexanes gradient to afford the title compound as a viscous yellow oil (330 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.38 (s, 9H), 2.69 (s, 2H), 2.78-2.90 (m, 1H), 2.99-3.12 (m, 1H), 3.28-3.35 (m, 2H), 3.64-3.71 (m, 1H), 3.78-3.89 (m, 4H), 4.29-4.35 (m, 2H), 5.21-5.26 (m, 1H), 6.61 (t, J=12 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 9.29 (s, 1H); LC-MS (LC-ES), M+H=449.

B. Racemic 3-(Benzo[d]thiazol-4-yloxy)-N-(morpholin-2-ylmethyl)azetidine-1-carboxamide

To methyl tert-butyl 2-((3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)methyl)morpholine-4-carboxylate (Intermediate 50A) (328 mg, 0.73 mmol) in DCM (4 mL) was added trifluoroacetic acid (1 mL, 13 mmol). The mixture was stirred at room temperature for 1.5 h and carefully neutralized with saturated aqueous NaHCO 3 . The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound as a yellow wax (48 mg, 19%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.70 (s, 2H), 2.94-2.99 (m, 2H), 3.27-3.40 (m, 2H), 3.66-3.72 (m, 1H), 3.81-3.88 (m, 3H), 4.12-4.22 (m, 1H), 4.27-4.34 (m, 2H), 5.19-5.25 (m, 1H), 6.46-6.54 (m, 1H), 6.86 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 9.29 (s, 1H); LC-MS (LC-ES), M+H=349.

Intermediate 51: 2-((trans)-4-Isothiocyanatocyclohexyl)propan-2-ol

To a stirred solution of 1,1′-thiocarbonyldiimidazole (125 mg, 0.701 mmol) in DCM (3 mL) was added a solution of 2-((trans)-4-aminocyclohexyl)propan-2-ol (75 mg, 0.48 mmol) in DCM (2 mL) dropwise. After 2 h, N,N-diisopropylethylamine (0.13 mL, 0.72 mmol) was added to the mixture. After stirring overnight, the mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 and filtered. Solvent was removed under reduced pressure. The remaining material was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (53 mg, 56%) as a yellow oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.00 (s, 6H), 1.00-1.08 (m, 2H), 1.12-1.20 (m, 1H), 1.36-1.48 (m, 2H), 1.74-1.82 (m, 2H), 2.08-2.13 (m, 2H), 3.64-3.73 (m, 1H), 4.08 (s, 1H); LC-MS (LC-ES), M+H—H 2 O=182.

Intermediate 52: tert-Butyl 4-(((4-nitrophenoxy)carbonyl)amino)piperidine-1-carboxylate

To 4-nitrophenyl chloroformate (755 mg, 3.74 mmol) in DCM (5 mL) at 0° C. was slowly added tert-butyl 4-aminopiperidine-1-carboxylate (500 mg, 2.50 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.9 mmol) in DCM (10 mL). The reaction was allowed to slowly warm to room temperature. After stirring overnight, the solvent was removed in vacuo, and the residue was purified on silica gel eluting with 0% to 50% EtOAc in hexanes gradient to afford the title compound as a white solid (720 mg, 79% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.28-1.34 (m, 2H), 1.38 (s, 9H), 1.76-1.82 (m, 2H), 2.77-2.90 (m, 2H), 3.49-3.58 (m, 1H), 3.81-3.88 (m, 2H), 7.39 (d, J=8 Hz, 2H), 8.08 (d, J=8 Hz, 1H), 8.22 (d, J=8 Hz, 2H); LC-MS (LC-ES) M+H-t-Bu=310.

Intermediate 53: 3-(Benzo[d]thiazol-4-yloxy)-N-(piperidin-4-yl)azetidine-1-carboxamide

To tert-butyl 4-(3-(benzo[d]thiazol-4-yloxy)azetidine-1-carboxamido)piperidine-1-carboxylate (Example 96) (193 mg, 0.446 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol). The mixture was stirred at room temperature for 1.5 h and carefully neutralized with saturated aqueous NaHCO 3 .and basified with aqueous 1 N NaOH. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound as a yellow solid (11 mg, 7%). The aqueous layer was concentrated and the resulting solid was suspended in DCM over the weekend, filtered, and the filtrate concentrated to give additional material as the title compound, a yellow solid (88 mg, 59%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.31-1.45 (m, 2H), 1.65-1.79 (m, 2H), 2.64-2.72 (m, 2H), 3.29-3.35 (m, 2H), 3.48-3.57 (m, 1H), 3.80-3.87 (m, 2H), 4.27-4.34 (m, 2H), 5.19-5.24 (m, 1H), 6.38 (d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 9.29 (s, 1H); LC-MS (LC-ES), M+H=333.

Intermediate 54: 2-(trans-4-Aminocyclohexyl)isothiazolidine 1,1-dioxide

A. Benzyl (trans-4-(3-chloropropylsulfonamido)cyclohexyl)carbamate

Benzyl (trans-4-aminocyclohexyl)carbamate (1.01 g, 4.07 mmol) was dissolved in DMF (8 mL) and N,N-diisopropylethylamine (1.04 g, 8.02 mmol) was added. 3-Chloropropane-1-sulfonyl chloride (0.786 g, 4.44 mmol) was added slowly, and the resulting mixture was stirred at room temperature for 3 hours. Water (50 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried to afford the title compound (1.42 g, 90% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.14-1.30 (m, 2H), 1.30-1.45 (m, 2H), 1.99-2.14 (m, 4H), 2.20-2.33 (m, 2H), 3.12-3.21 (m, 2H), 3.21-3.33 (m, 1H), 3.41-3.53 (m, 1H), 3.67 (t, J=6 Hz, 2H), 4.22 (d, J=8 Hz, 1H), 4.60 (d, J=7 Hz, 1H), 5.07 (s, 2H), 7.27-7.41 (m, 5H).

B. Benzyl (trans-4-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl)carbamate

Benzyl (trans-4-(3-chloropropylsulfonamido)cyclohexyl)carbamate (Intermediate 54A) (1.42 g, 3.65 mmol) was dissolved in THF (36 mL) and sodium hydride (60% dispersion in mineral oil) (0.325 g, 8.14 mmol) was added (gas evolution!). The solution was heated to 60° C. for 5 h. The mixture was cooled to room temperature and water (50 mL) and saturated aqueous ammonium chloride (25 mL) were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a 40%-80% ethyl acetate/heptane gradient, to give the title compound as a white solid (779 mg, 61%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.20-1.33 (m, 2H), 1.50-1.67 (m, 2H), 1.92-2.03 (m, 2H), 2.09 (d, J=12 Hz, 2H), 2.27-2.39 (m, 2H), 3.12 (t, J=8 Hz, 2H), 3.26 (t, J=7 Hz, 2H), 3.36-3.55 (m, 2H), 4.62 (d, J=7 Hz, 1H), 5.08 (s, 2H), 7.28-7.41 (m, 5H).

C. 2-(trans-4-Aminocyclohexyl)isothiazolidine 1,1-dioxide

Palladium on carbon (233 mg, 2.21 mmol) was added to benzyl (trans-4-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl)carbamate (Intermediate 54B) (0.779 g, 2.21 mmol) under a nitrogen atmosphere with enough methanol to wet the catalyst. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 2 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (497 mg, quantitative) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.03-1.19 (m, 2H), 1.40-1.58 (m, 2H), 1.67-1.87 (m, 4H), 2.13-2.24 (m, 2H), 3.06-3.26 (m, 8H).

Intermediate 55: 1-(trans-4-Aminocyclohexyl)-3-methylimidazolidin-2-one

A. Benzyl (trans-4-(3-(2-hydroxyethyl)-3-methylureido)cyclohexyl)carbamate

To trans-4-(((benzyloxy)carbonyl)amino)cyclohexanecarboxylic acid (2.43 g, 8.76 mmol) suspended in toluene (20 mL) was added N,N-diisopropylethylamine (2.30 g, 17.8 mmol) followed by diphenyl phosphoryl azide (2.68 g, 9.74 mmol). The mixture was heated to 100° C. for 60 minutes, and 2-(methylamino)ethanol (795 mg, 10.6 mmol) was added. After 75 minutes, the mixture was cooled to room temperature, washed with water (100 mL) and brine (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 10% isopropanol in ethyl acetate, to give the title compound as a white solid (1.86 g, 61%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.14-1.30 (m, 5H), 1.69-1.86 (m, 5H), 2.79 (s, 3H), 3.15-3.26 (m, 3H), 3.40-3.50 (m, 2H), 4.72 (t, J=5 Hz, 1H), 4.99 (s, 2H), 5.88 (d, J=7 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.26-7.41 (m, 4H).

B. Benzyl (trans-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)carbamate

Benzyl (trans-4-(3-(2-hydroxyethyl)-3-methylureido)cyclohexyl)carbamate (Intermediate 55A) (1.86 g, 5.32 mmol) was dissolved in THF (20 mL) and cooled to 0° C. Potassium tert-butoxide (1.49 g, 13.3 mmol) was added followed by p-toluenesulfonyl chloride (1.23 g, 6.44 mmol). The mixture was allowed to slowly warm to room temperature and stir overnight. Water (100 mL) and brine (20 mL) were added, and the mixture was extracted with ethyl acetate (4×20 mL). The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate, to give the title compound as a white solid (1.19 g, 67%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.28 (qd, J=13, 3 Hz, 2H), 1.42-1.57 (m, 2H), 1.75 (d, J=12 Hz, 2H), 2.00-2.12 (m, 2H), 2.76 (s, 3H), 3.21-3.28 (m, 4H), 3.38-3.52 (m, 1H), 3.65-3.79 (m, 1H), 4.70 (d, J=7 Hz, 1H), 5.08 (s, 2H), 7.28-7.40 (m, 5H).

C. 1-(trans-4-Aminocyclohexyl)-3-methylimidazolidin-2-one

Palladium on carbon (130 mg, 0.22 mmol) was added to benzyl (trans-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)carbamate (Intermediate 55B) (402 mg, 1.21 mmol) under a nitrogen atmosphere with enough methanol to wet the catalyst. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 2 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (244 mg, quantitative) as a colorless film. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.06-1.21 (m, 2H), 1.35-1.49 (m, 2H), 1.49-1.58 (m, 2H), 1.81 (d, J=12 Hz, 2H), 2.53-2.57 (m, 1H), 2.61 (s, 3H), 3.18 (s, 4H), 3.40-3.45 (m, 1H).

Intermediate 56: 3-(trans-4-Aminocyclohexyl)oxazolidin-2-one

A. Benzyl (2-((tert-butyldimethylsilyl)oxy)ethyl) trans-cyclohexane-1,4-diyldicarbamate

To 2-((tert-butyldimethylsilyl)oxy)ethanol (1.08 g, 6.11 mmol) in DCM (12 mL) N,N-diisopropylethylamine (1.55 g, 12.0 mmol) was added, followed by triphosgene (602 mg, 2.03 mmol). After 60 minutes, the mixture was concentrated, and the residue was added slowly to a suspension of benzyl (trans-4-aminocyclohexyl)carbamate (1.02 g, 4.10 mmol) in DMF (8 mL). After stirring overnight, the mixture was poured into water (100 mL) and the precipitated solid was collected by filtration, washed with water and dried. The material was purified by silica gel chromatography, eluting with a 20%-40% ethyl acetate/heptane gradient, to give the title compound as a white solid (680 mg, 37%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.02 (s, 6H), 0.83 (s, 9H), 1.18 (t, J=9 Hz, 4H), 1.68-1.83 (m, 4H), 3.11-3.24 (m, 2H), 3.64-3.75 (m, 2H), 3.94 (t, J=5 Hz, 2H), 4.97 (s, 2H), 7.04 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 7.24-7.39 (m, 5H).

B. Benzyl (2-hydroxyethyl) trans-cyclohexane-1,4-diyldicarbamate

To benzyl (2-((tert-butyldimethylsilyl)oxy)ethyl) trans-cyclohexane-1,4-diyldicarbamate (Intermediate 56A) (900 mg, 2.00 mmol) in THF (4 mL), 1.0 M TBAF in THF (4.0 mL, 4.0 mmol) was added. After 2 hours, water (100 mL) was added, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a 50%-90% ethyl acetate/heptane gradient, to give the title compound as a white solid (507 mg, 76%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.10-1.29 (m, 4H), 1.69-1.88 (m, 4H), 3.19 (br s, 2H), 3.47-3.55 (m, 2H), 3.92 (t, J=5 Hz, 2H), 4.68 (t, J=5 Hz, 1H), 4.99 (s, 2H), 7.05 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.25-7.41 (m, 5H).

C. Benzyl (trans-4-(2-oxooxazolidin-3-yl)cyclohexyl)carbamate

Benzyl (2-hydroxyethyl) trans-cyclohexane-1,4-diyldicarbamate (Intermediate 56B) (507 mg, 1.51 mmol) was dissolved in THF (9 mL) and cooled to 0° C. Potassium tert-butoxide (423 mg, 3.77 mmol) was added, followed by p-toluenesulfonyl chloride (345 mg, 1.81 mmol). The mixture was allowed to slowly warm to room temperature and stir 3 days. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×15 mL). The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a 50%-90% ethyl acetate/heptane gradient, to give the title compound as a white solid (346 mg, 72%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.27 (qd, J=13, 3 Hz, 2H), 1.45-1.60 (m, 2H), 1.60-1.72 (m, 2H), 1.87 (d, J=12 Hz, 2H), 3.20-3.31 (m, 1H), 3.36-3.42 (m, 1H), 3.47 (t, J=8 Hz, 2H), 4.23 (t, J=8 Hz, 2H), 5.00 (s, 2H), 7.22 (d, J=8 Hz, 1H), 7.27-7.44 (m, 5H).

D. 3-(trans-4-Aminocyclohexyl)oxazolidin-2-one

Palladium on carbon (123 mg, 0.12 mmol) was added to benzyl (trans-4-(2-oxooxazolidin-3-yl)cyclohexyl)carbamate (Intermediate 56C) (346 mg, 1.09 mmol) under a nitrogen atmosphere with enough methanol to wet the catalyst. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred overnight under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (197 mg, 99%) as a colorless gel. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.03-1.19 (m, 2H), 1.38-1.55 (m, 2H), 1.62 (d, J=11 Hz, 2H), 1.81 (d, J=12 Hz, 2H), 2.52-2.63 (m, 1H), 3.34-3.42 (m, 1H), 3.42-3.52 (m, 2H), 4.16-4.31 (m, 2H).

Intermediate 57: trans-4-Amino-1-methylcyclohexanol

A. Benzyl (trans-4-hydroxy-4-methylcyclohexyl)carbamate

Cerium(III) chloride heptahydrate (3.12 g, 8.39 mmol) was dried at 140° C. under high vacuum for 60 minutes, and then was cooled to room temperature, while remaining under vacuum overnight. The solid was placed under a nitrogen atmosphere and THF (16 mL) was added. The slurry was stirred for 90 minutes, and then cooled to −78° C. A 1.6 M solution of methyllithium in diethyl ether (5.10 mL, 8.16 mmol) was added. After 60 minutes, benzyl (4-oxocyclohexyl)carbamate (1.00 g, 4.05 mmol) in THF (5 mL) was added. After 2 hours, the mixture was poured into saturated aqueous ammonium chloride (50 mL) and water (50 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL), and the combined organics were dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a 40%-70% ethyl acetate-heptane gradient, to give the title compound as a white solid (524 mg, 49%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.20-1.31 (m, 4H), 1.33-1.46 (m, 2H), 1.46-1.69 (m, 4H), 1.88-2.02 (m, 2H), 3.57-3.72 (m, 1H), 4.70 (br s, 1H), 5.09 (br s, 2H), 7.28-7.43 (m, 5H).

B. trans-4-Amino-1-methylcyclohexanol

Palladium on carbon (217 mg, 0.20 mmol) was added to benzyl (trans-4-hydroxy-4-methylcyclohexyl)carbamate (Intermediate 57A) (524 mg, 1.99 mmol) under a nitrogen atmosphere with enough methanol to wet the catalyst. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 1 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (257 mg, quantitative) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.08 (s, 3H), 1.09-1.19 (m, 2H), 1.26-1.38 (m, 2H), 1.45-1.56 (m, 2H), 1.59-1.72 (m, 2H), 2.59-2.66 (m, 1H).

Intermediate 58: 1-(Pyrimidin-2-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(pyrimidin-2-yl)azetidin-3-yl)carbamate

To a microwave reaction vial with tert-butyl azetidin-3-ylcarbamate hydrochloride (209 mg, 1.00 mmol) in NMP (2 mL) was added 2-chloropyrimidine (115 mg, 1.00 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol). The mixture was heated in a microwave (130° C.) for 2.5 h, cooled, diluted with water and MeOH, and loaded onto a semi-prep HPLC (NH 4 OH as modifier) to afford the title compound as a pale yellow solid (147 mg, 59% yield). 1 H NMR (400 MHz, CD 3 OD) δ 1.45 (s, 9H), 3.93 (dd, J=9, 5 Hz, 2H), 4.36 (t, J=8 Hz, 2H), 4.42-4.57 (m, 1H), 6.67 (t, J=5 Hz, 1H), 8.31 (d, J=5 Hz, 2H); LC-MS (LC-ES) M+H=251.

B. 1-(Pyrimidin-2-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(pyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 58A) (145 mg, 0.51 mmol) in MeOH (2 mL) was added 4 N HCl in dioxane (4 mL, 16 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give the title compound as a pale yellow solid (160 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.32-4.40 (m, 1H), 4.40-4.46 (m, 2H), 4.72 (dd, J=11, 8 Hz, 2H), 7.07 (t, J=5 Hz, 1H), 8.65 (d, J=5 Hz, 2H); LC-MS (LC-ES) M+H=151.

Intermediate 59: (trans)-3-(6-Fluorobenzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid

A. (cis)-Methyl 3-((methylsulfonyl)oxy)cyclobutanecarboxylate

To a DCM (20 ml) solution of (cis)-methyl 3-hydroxycyclobutanecarboxylate (2.00 g, 15.4 mmol) at 0° C., triethylamine (4.71 ml, 33.8 mmol) was added, followed by methanesulfonyl chloride (1.94 g, 17.0 mmol). After 3 h, the mixture was warmed to room temperature. After 1 h, a precipitate was removed by filtration, the filtrate was concentrated in vacuo, and the resulting residue was purified on silica gel, eluting with a 10% to 60% EtOAc-hexanes gradient, to afford the title compound (3.01 g, 94%), a colorless liquid. 1 H NMR (400 MHz, CDCl 3 ) δ 2.55-2.65 (m, 2H), 2.68-2.82 (m, 3H), 3.02 (s, 3H), 3.73 (s, 3H), 4.90-5.01 (m, 1H).

B. (trans)-Methyl 3-((6-fluorobenzo[d]thiazol-4-yl)oxy)cyclobutanecarboxylate

A mixture of 6-fluorobenzo[d]thiazol-4-ol (400 mg, 2.36 mmol), (cis)-methyl 3-((methylsulfonyl)oxy)cyclobutanecarboxylate (Intermediate 59A) (492 mg, 2.36 mmol) and cesium carbonate (924 mg, 2.84 mmol) in DMF (7.5 mL) was stirred at 85° C. After stirring overnight, the reaction was cooled to room temperature, diluted with water; extracted with ethyl acetate (3×) and the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel eluting with a 10%-60% EtOAc-hexanes gradient to give the title compound (370 mg, 56%) as a thick oil which slowly solidified. 1 H NMR (400 MHz, CD 3 OD) δ 2.57-2.69 (m, 2H), 2.80-2.91 (m, 2H), 3.25-3.33 (m, 1H), 3.76 (s, 3H), 5.14 (t, J=6 Hz, 1H), 6.71 (d, J=11 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 9.12 (s, 1H); LC-MS (LC-ES) M+H=282.

C. (trans)-3-(6-Fluorobenzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-((6-fluorobenzo[d]thiazol-4-yl)oxy)cyclobutanecarboxylate (Intermediate 59B) (680 mg, 2.42 mmol) in THF (6 mL) and water (2 mL) was added LiOH (116 mg, 4.80 mmol). The reaction mixture was stirred at room temperature overnight. A portion of the solvents were removed in vacuo, and the remainder was partitioned between EtOAc and water. The aqueous layer was separated and adjusted to pH=4 with the addition of aqueous citric acid, followed by extraction with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO 4 and concentrated to give the title compound (582 mg, 90%) as a light tan solid. 1 H NMR (400 MHz, CD 3 OD) δ 2.57-2.69 (m, 2H), 2.80-2.95 (m, 2H), 3.19-3.31 (m, 1H), 5.01-5.24 (m, 1H), 6.73 (d, J=11 Hz, 1H), 7.39 (d, J=7 Hz, 1H), 8.90-9.31 (m, 1H); LC-MS (LC-ES) M+H=268.

Intermediate 60: 2-(3-Aminoazetidin-1-yl)-5-methylpyridine 1-oxide hydrochloride

A. 2-(3-((tert-Butoxycarbonyl)amino)azetidin-1-yl)-5-methylpyridine 1-oxide

To a microwave reaction vial with tert-butyl azetidin-3-ylcarbamate hydrochloride (522 mg, 2.5 mmol) in ethanol (8 mL) was added 2-chloro-5-methylpyridine 1-oxide (359 mg, 2.5 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol). The mixture was heated in a microwave at 120° C. for 2 h, cooled, and then another portion (2.5 mmol) of both tert-butyl azetidin-3-ylcarbamate hydrochloride and N,N-diisopropylethylamine were added. The mixture was heated in a microwave at 125° C. for 3 h, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 0%-40% MeOH-DCM gradient to give the title compound (335 mg, 31%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 2.24 (s, 3H), 3.67-3.83 (m, 2H), 4.00-4.06 (m, 2H), 4.44-4.54 (m, 1H), 6.66 (d, J=9 Hz, 1H), 7.29-7.38 (m, 1H), 7.86 (s, 1H); LC-MS (LC-ES) M+H=280.

B. 2-(3-Aminoazetidin-1-yl)-5-methylpyridine 1-oxide hydrochloride

To 2-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)-5-methylpyridine 1-oxide (Intermediate 60A) (330 mg, 1.18 mmol) in MeOH (3 mL) was added 4 N HCl in dioxane (0.3 mL, 1.2 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo to give the title compound as a white solid (310 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.32 (s, 3H), 4.28-4.40 (m, 1H), 4.57 (dd, J=11, 4 Hz, 2H), 4.83-4.89 (m, 2H), 7.00 (d, J=9 Hz, 1H), 7.89 (dd, J=9, 2 Hz, 1H), 8.09 (s, 1H); LC-MS (LC-ES) M+H=180.

Intermediate 61: 4-(Azetidin-3-yloxy)-6-fluorobenzo[d]thiazole hydrochloride

A. tert-Butyl 3-((6-fluorobenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (2.67 g, 10.6 mmol) and 6-fluorobenzo[d]thiazol-4-ol (1.50 g, 8.87 mmol) in DMF (19 mL) was added cesium carbonate (3.47 g, 10.6 mmol). The mixture was heated to 85° C. overnight, poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 20%-70% EtOAc-hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound contaminated with the mesylate starting material. This material was purified on silica gel eluting with a 5%-60% EtOAc-hexanes gradient to give the title compound (1.30 g, 45%) as a colorless foam. 1 H NMR (400 MHz, CD 3 OD) δ 1.48 (s, 9H), 4.12 (d, J=7 Hz, 2H), 4.41-4.50 (m, 2H), 5.21-5.32 (m, 1H), 6.74 (dd, J=11, 2 Hz, 1H), 7.48 (dd, J=8, 2 Hz, 1H), 9.17 (s, 1H); LC-MS (LC-ES) M+H=325.

B. 4-(Azetidin-3-yloxy)-6-fluorobenzo[d]thiazole hydrochloride

To tert-butyl 3-((6-fluorobenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxylate (Intermediate 61A) (1.30 g, 4.01 mmol) in DCM (6 mL), was added 4 M HCl in dioxane (12 mL, 48 mmol). The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo to give the title compound as an off white solid (1.26 g, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.33 (dd, J=12, 4 Hz, 2H), 4.67 (dd, J=12, 7 Hz, 2H), 5.44-5.51 (m, 1H), 6.88 (dd, J=10, 2 Hz, 1H), 7.56 (dd, J=8, 2 Hz, 1H), 9.25 (s, 1H); LC-MS (LC-ES) M+H=225.

Intermediate 62: (2-(3-Aminoazetidin-1-yl)pyrimidin-5-yl)methanol dihydrochloride

A. tert-Butyl (1-(5-(hydroxymethyl)pyrimidin-2-yl)azetidin-3-yl)carbamate

To a microwave reaction vial with tert-butyl azetidin-3-ylcarbamate hydrochloride (433 mg, 2.1 mmol) in acetonitrile (10 mL) was added (2-chloropyrimidin-5-yl)methanol (300 mg, 2.1 mmol) and N,N-diisopropylethylamine (1.8 mL, 10 mmol). The mixture was heated in a microwave at 130° for 3 h, cooled and concentrated. The resulting residue was purified on silica gel eluting with a 30%-100% EtOAc:EtOH (3:1) in hexanes gradient to give the title compound (415 mg, 71%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 3.96 (dd, J=9, 6 Hz, 2H), 4.38 (t, J=8 Hz, 2H), 4.48 (s, 2H), 4.48-4.57 (m, 1H), 8.34 (s, 2H); LC-MS (LC-ES) M+H=281.

B. (2-(3-Aminoazetidin-1-yl)pyrimidin-5-yl)methanol dihydrochloride

To tert-butyl (1-(5-(hydroxymethyl)pyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 62A) (410 mg, 1.46 mmol) in DCM (6 mL) was added 4 N HCl in dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature for 3 h, and the solvent was removed in vacuo to give the title compound as a pale yellow solid (382 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.31-4.51 (m, 3H), 4.61 (s, 2H), 4.71-4.79 (m, 2H), 8.64 (s, 2H); LC-MS (LC-ES) M+H=181.

Intermediate 63: Racemic 4-Nitrophenyl ((cis)-4-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)carbamate

A. 4-(Dibenzylamino)cyclohexanone

To a DCM (160 mL) solution of oxalyl chloride (9.1 mL, 104 mmol) cooled to −78° C. was added, dropwise over 15 min, a solution of DMSO (14.5 mL, 2.04 mmol) in DCM (16 mL), keeping the reaction below −68° C. for the duration. After 15 min, a DCM (100 mL) solution of (trans)-4-(dibenzylamino)cyclohexanol (20 g, 67.7 mmol) was added dropwise over 15 min, keeping the temperature below −68° C. for the duration. After 30 min, triethylamine (30 mL, 215 mmol) was added over 15 min, keeping the temperature below −70° C. for the duration. After 1 h, the reaction was warmed to −3° C., diluted with diethyl ether (500 mL), and washed with 1:1 brine:water (2×250 mL). The organic layer was dried over MgSO 4 , filtered, concentrated, diluted with heptane (50 mL) and concentrated again to remove residual DCM. The residue was triturated with heptane (50 mL), aged 1 h at 0° C., and the resulting solid was collected by filtration, washed with heptanes and dried to give the title compound as an off white solid (17.9 g, 90%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.73-1.88 (m, 2H), 2.06 (dd, J=10, 3 Hz, 2H), 2.13-2.23 (m, 2H), 2.25-2.37 (m, 2H), 2.87-2.99 (m, 1H), 3.61 (s, 4H), 7.15-7.24 (m, 2H), 7.27-7.33 (m, 4H), 7.34-7.41 (m, 4H).

B. Racemic Methyl 2-((4-(dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropanoate

Methyl 2-amino-3,3,3-trifluoropropanoate hydrochloride (820 mg, 4.24 mmol) was added to 4-(dibenzylamino)cyclohexanone (Intermediate 63A) (1.24 g, 4.24 mmol) in 1,2-dichloroethane (21 mL) at room temperature and stirred for 5 minutes, followed by 4 Å molecular sieves (10 g). After 2 h, sodium bicarbonate (356 mg, 4.24 mmol) and sodium triacetoxyborohydride (0.898 g, 4.24 mmol) were added, and the reaction mixture was stirred over the weekend. The reaction mixture was filtered, diluted with EtOAc, washed with saturated aqueous NaHCO 3 and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 2:3 EtOAc:hexanes to give the title compound (730 mg, 40% yield) as a mixture of cis and trans isomers. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.98-1.20 (m, 2H), 1.31-2.01 (m, 6H), 2.37-2.47 (m, 1H), 2.48-2.58 (m, 1H), 2.75 (br s, 1H), 3.59 (s, 2H), 3.64 (s, 2H), 3.74-3.84 (m, 1H), 3.84 (s, 3H), 7.19-7.25 (m, 2H), 7.27-7.33 (m, 4H), 7.34-7.42 (m, 4H); LC-MS (LC-ES) M+H=435.

C. Racemic 2-(((trans)-4-(Dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropan-1-ol and 2-(((cis)-4-(Dibenzylamino)cyclohexyl)amino)-3.3.3-trifluoropropan-1-ol

1 M Lithium aluminum hydride in diethyl ether (2.1 mL, 2.1 mmol) was added to methyl 2-((4-(dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropanoate (Intermediate 63B) (690 mg, 1.59 mmol) in THF (10 mL). After 30 min, the mixture was quenched with water dropwise, stirred for 15 min and diluted with EtOAc. After partitioning between two layers, 1 N NaOH was added to the aqueous layer, which was further extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated and the residue was purified on silica gel, eluting with 5% to 40% EtOAc in hexanes to give 2-(((trans)-4-(dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropan-1-ol as a white solid (284 mg, 44%) and 2-(((cis)-4-(dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropan-1-ol as a white solid (317 mg, 49%).

2-(((trans)-4-(Dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropan-1-ol

1 H NMR (400 MHz, CD 3 OD) δ 1.35 (t, J=13 Hz, 2H), 1.60 (d, J=11 Hz, 2H), 1.72-1.94 (m, 4H), 2.39-2.54 (m, 1H), 2.94 (br s, 1H), 3.17 (d, J=6 Hz, 1H), 3.55-3.69 (m, 5H), 3.78 (dd, J=12, 4 Hz, 1H), 7.13-7.20 (m, 2H), 7.26 (t, J=7 Hz, 4H), 7.35 (d, J=7 Hz, 4H); LC-MS (LC-ES) M+H=407.

2-(((cis)-4-(Dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropan-1-ol

1 H NMR (400 MHz, CD 3 OD) δ 0.89-1.11 (m, 2H), 1.37-1.58 (m, 2H), 1.80-2.00 (m, 4H), 2.37-2.66 (m, 2H), 3.17-3.25 (m, 1H), 3.52-3.67 (m, 5H), 3.75 (dd, J=12, 4 Hz, 1H), 7.13-7.21 (m, 2H), 7.21-7.29 (m, 4H), 7.29-7.40 (m, 4H); LC-MS (LC-ES) M+H=407. LCMS in GADR but Not in notebook

D. Racemic 2-(cis)-((4-Aminocyclohexyl)amino)-3,3,3-trifluoropropan-1-ol

2-(((cis)-4-(Dibenzylamino)cyclohexyl)amino)-3,3,3-trifluoropropan-1-ol (Intermediate 63C) (0.31 g, 0.76 mmol) and 20 wt % Pearlman's catalyst (53.6 mg, 0.076 mmol) were stirred in ethanol (20 mL) and purged with hydrogen on a Parr apparatus before shaking under a 40 psi hydrogen atmosphere overnight. The reaction was purged with nitrogen, filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (166 mg, 96%). 1 H NMR (400 MHz, CD 3 OD) δ 1.03-1.26 (m, 4H), 1.80-2.13 (m, 4H), 2.57-2.69 (m, 2H), 3.22-3.34 (m, 1H), 3.60-3.67 (m, 1H), 3.72-3.95 (m, 1H).

E. Racemic 4-Nitrophenyl ((cis)-4-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)carbamate

To 4-nitrophenyl chloroformate (122 mg, 0.604 mmol) in acetonitrile (2 mL) at 0° C. was slowly added 2-(cis)-((4-aminocyclohexyl)amino)-3,3,3-trifluoropropan-1-ol (Intermediate 63D) (130 mg, 0.575 mmol) in acetonitrile (2 mL). After 1 h, sodium bicarbonate (97 mg, 1.2 mmol) was added, and the mixture was allowed to warm to room temperature. After stirring overnight, the solvent was removed in vacuo, and the residue was diluted with EtOAc, washed with brine, dried over MgSO 4 , filtered and concentrated. A small amount of DCM was added to the residue, and the resulting solid was collected by filtration to afford the title compound white solid (163 mg, 73% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.90-1.35 (m, 4H), 1.75-2.01 (m, 4H), 2.44-2.54 (m, 3H), 3.16-3.30 (m, 2H), 3.43-3.57 (m, 1H), 3.62-3.69 (m, 1H), 4.97 (br s, 1H), 7.40 (d, J=9 Hz, 2H), 8.26 (d, J=9 Hz, 2H); LC-MS (LC-ES) M+H=392.

Intermediate 64: Racemic 2-(((trans)-4-Aminocyclohexyl)amino)-3,3,3-trifluoropropan-1-ol dihydrochloride

A. Racemic Ethyl 2-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-3,3,3-trifluoropropanoate

tert-Butyl ((trans)-4-aminocyclohexyl)carbamate (1.00 g, 4.67 mmol) was added to ethyl 3,3,3-trifluoro-2-oxopropanoate (1.02 g, 5.13 mmol) in 1,2-dichloroethane (23 mL) at room temperature and stirred for 5 minutes, followed by acetic acid (14 mg, 0.23 mmol) and 4 Å molecular sieves (8 g). After 2 h, sodium triacetoxyborohydride (0.989 g, 4.67 mmol) were added, and the reaction mixture was stirred overnight. The reaction mixture was filtered, diluted with EtOAc, washed with saturated aqueous NaHCO 3 and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 10%-60% EtOAc-hexanes to give the title compound (87 mg, 5% yield). 1 H NMR (400 MHz, CD 3 OD) δ 1.31 (d, J=10 Hz, 2H), 1.38 (t, J=7 Hz, 3H), 1.46 (s, 9H), 1.59-1.72 (m, 2H), 1.73-1.84 (m, 2H), 2.00 (d, J=11 Hz, 2H), 3.31-3.46 (m, 2H), 3.59 (t, J=5 Hz, 1H), 4.42 (q, J=7 Hz, 2H).

B. Racemic tert-butyl ((trans)-4-(1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)carbamate

1 M Lithium aluminum hydride in diethyl ether (0.31 ml, 0.31 mmol) was added to ethyl 2-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-3,3,3-trifluoropropanoate (Intermediate 64A) (87 mg, 0.24 mmol) in THF (1.5 ml) at 0° C. After 1 h, the reaction was quenched carefully with water and then 1 N aqueous NaOH. The mixture was taken up in EtOAc, dried over MgSO 4 , concentrated and the residue was purified on silica gel, eluting with 10% to 70% EtOAc in hexanes, to afford the title compound as a white solid (84 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.08-1.30 (m, 4H), 1.45 (s, 9H), 1.83-2.03 (m, 4H), 2.51-2.68 (m, 1H), 3.21-3.32 (m, 2H), 3.62 (dd, J=12, 6 Hz, 1H), 3.77 (d, J=4 Hz, 1H).

C. Racemic 2-(((trans)-4-Aminocyclohexyl)amino)-3,3,3-trifluoropropan-1-ol dihydrochioride

To tert-butyl ((trans)-4-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)cyclohexyl)carbamate (Intermediate 64B) (85 mg, 0.26 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give the title compound (79 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.50-1.83 (m, 4H), 2.15-2.28 (m, 2H), 2.30-2.41 (m, 2H), 3.15-3.25 (m, 1H), 3.42-3.53 (m, 1H), 3.55-3.61 (m, 1H), 3.65-3.72 (m, 2H), 3.74-3.80 (m, 1H), 3.98-4.15 (m, 2H), 4.36-4.52 (m, 1H).

Intermediate 65: 4-Nitrophenyl ((trans)-4-(2-methoxyethoxy)cyclohexyl)carbamate

To 4-nitrophenyl chloroformate (326 mg, 1.62 mmol) in acetonitrile (5 mL) at 0° C. was slowly added (trans)-4-(2-methoxyethoxy)cyclohexanamine (Intermediate 39) (200 mg, 1.15 mmol) in acetonitrile (5 mL). After 30 min, sodium bicarbonate (194 mg, 2.31 mmol) was added, and the mixture was allowed to warm to room temperature. After 1 h, the solvent was removed in vacuo, and the residue was purified on silica gel, eluting with a 0%-60% EtOAc in hexanes gradient to give the title compound as a white solid (280 mg, 72%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.15-1.32 (m, 4H), 1.82-1.89 (m, 2H), 1.90-2.03 (m, 2H), 2.51 (dt, J=4, 2 Hz, 1H), 3.21-3.24 (m, 1H), 3.24 (s, 3H), 3.39-3.45 (m, 2H), 3.49-3.56 (m, 2H), 7.36-7.43 (m, 2H), 8.04 (d, J=8 Hz, 1H), 8.24-8.31 (m, 2H); LC-MS (LC-ES) M+H=339.

Intermediate 66: 4-Nitrophenyl (1-(pyrimidin-2-yl)azetidin-3-yl)carbamate

To 4-nitrophenyl chloroformate (172 mg, 0.853 mmol) in acetonitrile (2 mL) at 0° C. was slowly added 1-(pyrimidin-2-yl)azetidin-3-amine dihydrochloride (Intermediate 58) (136 mg, 0.61 mmol) in acetonitrile (2 mL). After 30 min, pyridine (145 mg, 1.83 mmol) was added, and the mixture was allowed to warm to room temperature. After 1 h, the solvent was removed in vacuo, and the residue was purified on silica gel, eluting with a 0%-60% EtOAc in hexanes gradient to give the title compound as a white solid (86 mg, 45%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 4.00 (dd, J=9, 6 Hz, 2H), 4.26-4.40 (m, 2H), 4.48-4.60 (m, 1H), 6.71 (t, J=5 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 8.28 (d, J=9 Hz, 2H), 8.34-8.42 (m, 2H), 8.79 (d, J=8 Hz, 1H); LC-MS (LC-ES) M+H=316.

Intermediate 67: (cis)-3-Amino-1-methylcyclobutanol hydrochloride

A. tert-Butyl (cis)-3-hydroxy-3-methylcyclobutyl)carbamate

Cerium(III) chloride heptahydrate (10.06 g, 27.0 mmol) was dried at 140° C. under high vacuum for 17 h, and then was cooled to room temperature while remaining under vacuum. The solid was placed under a nitrogen atmosphere, cooled to 0° C. and THF (60 mL) was added. The ice bath was removed, and the slurry was stirred for 1 h, and then cooled to −78° C. A 1.6 M solution of methyllithium in diethyl ether (16.9 mL, 27.0 mmol) was added at a rate to keep the temperature below −70° C. After 90 minutes, tert-butyl (3-oxocyclobutyl)carbamate (2.50 g, 13.5 mmol) in THF (15 mL) was added at a rate to keep the temperature below −70° C. After 3 hours, the mixture was allowed to slowly warm to room temperature. After stirring overnight, the mixture was poured into saturated aqueous ammonium chloride (100 mL) and water (100 mL), stirred 10 min and filtered. The filtrate was extracted with ethyl acetate (2×), and the combined organics were dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a 20%-100% ethyl acetate-hexanes gradient, to give the title compound as a colorless solid (1.05 g, 39%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.37 (s, 3H), 1.44 (s, 9H), 1.98 (td, J=9, 3 Hz, 2H), 2.46-2.54 (m, 2H), 3.72 (quin, J=8 Hz, 1H), 4.68 (br s, 1H).

B. (cis)-3-Amino-1-methylcyclobutanol hydrochloride

To tert-butyl (cis)-3-hydroxy-3-methylcyclobutyl)carbamate (Intermediate 67B) (1.04 g, 5.17 mmol) in methanol (18.45 mL) was added 4 N HCl in dioxane (5.81 mL, 23.3 mmol). The mixture was stirred overnight, more 4 N HCl in dioxane (1.30 mL, 5.17 mmol) was added, and after three hours, the solvent was removed in vacuo. The resulting residue was redissolved and concentrated with both dioxane and diethyl ether to give the title compound (786 mg, 99%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.14-1.24 (m, 3H), 1.88 (t, J=10 Hz, 2H), 2.10-2.20 (m, 2H), 3.42-3.55 (m, 1H), 4.85 (s, 1H).

Intermediate 68: Racemic 2-((trans)-5-Aminotetrahydro-2H-pyran-2-yl)propan-2-ol hydrochloride

To 2-((trans)-5-(d ibenzylamino)tetrahydro-2H-pyran-2-yl)propan-2-ol (Intermediate 341) (265 mg, 0.781 mmol) and EtOH (7 mL) under a N 2 atmosphere was added 20% palladium hydroxide (137 mg, 0.195 mmol), and the vessel was evacuated and flushed with N 2 and then stirred under 40 psi H 2 for 24 h. The vessel was evacuated and flushed with N 2 and the mixture filtered through a pad of Celite® and rinsed with EtOH and EtOAc. To the filtrate, 4 N HCl in dioxane (1 mL, 4 mmol) was added. This mixture was concentrated to give the title compound as a white foam (147 mg, 96% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.98 (s, 3H), 1.04 (s, 3H), 1.24-1.38 (m, 1H), 1.41-1.54 (m, 1H), 1.75 (d, J=13 Hz, 1H), 2.06 (d, J=12 Hz, 1H), 2.87-3.04 (m, 2H), 3.22 (t, J=11 Hz, 1H), 3.95-4.07 (m, 1H); LC-MS (ES-MS) M+H=160.

Intermediate 69: (trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxylate

Triphenylphosphine (6.14 g, 23.4 mmol) was added to a solution of 2-methoxy-5-fluorophenol (2.25 g, 15.6 mmol) in tetrahydrofuran (40 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (2.44 g, 18.7 mmol) was added, followed by DIAD (4.6 mL, 23 mmol). The reaction mixture was then warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organics were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 30%-70% EtOAc-hexanes gradient to give the title compound as a colorless, thick oil (3.6 g, 91%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.52-2.64 (m, 2H), 2.74-2.83 (m, 2H), 3.15-3.27 (m, 1H), 3.76 (s, 3H), 3.86 (s, 3H), 4.90 (t, J=7 Hz, 1H), 6.48 (dd, J=10, 3 Hz, 1H), 6.62 (td, J=8, 3 Hz, 1H), 6.81 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) peak at T=0.78 min.

B. (trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2-(difluoromethoxy)-5-fluorophenoxy)cyclobutanecarboxylate (Intermediate 69A) (3.70 g, 14.6 mmol) in THF (20 mL) was added a solution of LiOH (1.83 g, 43.7 mmol) in water (10 mL). After 3 h, the mixture was adjusted to pH=5 with concentrated HCl, and the resulting solid was collected by filtration and then azeotroped with MeOH to give the title compound (2.51 g, 72%). 1 H NMR (400 MHz, CD 3 OD) δ 2.36-2.46 (m, 2H), 2.69 (ddd, J=13, 7, 4 Hz, 2H), 3.11 (dt, J=10, 5 Hz, 1H), 3.79 (s, 3H), 4.84 (t, J=7 Hz, 1H), 6.55-6.65 (m, 2H), 6.89 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) M−H=239.

Intermediate 70: Racemic (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(pyrrolidin-3-yl)cyclobutanecarboxamide hydrochloride

To tert-butyl 3-((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)pyrrolidine-1-carboxylate (Example 143) (90 mg, 0.22 mmol) in DCM (1 mL) was added 4 N HCl in dioxane (3 mL, 12 mmol). The mixture was stirred for 2 h and the solvent was removed in vacuo to give the title compound (786 mg, 99%) as a light tan solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.98-2.09 (m, 1H), 2.26-2.38 (m, 1H), 2.38-2.49 (m, 2H), 2.61-2.71 (m, 2H), 3.09-3.18 (s, 1H), 3.20-3.29 (m, 1H), 3.30-3.40 (m, 2H), 3.42-3.57 (m, 2H), 3.81 (s, 3H), 4.37-4.42 (m, 1H), 4.81-4.90 (m, 1H), 6.55 (dd, J=10, 3 Hz, 1H), 6.58-6.66 (m, 1H), 6.92 (dd, J=9, 5 Hz, 1H), 8.32 (br s, 1H); LC-MS (ES-MS) M+H=309.

Intermediate 71: (trans)-N-(Azetidin-3-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide, trifluoroacetic acid salt

A. tert-Butyl 3-((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)azetidine-1-carboxylate

To a DMF (5 mL) solution of (trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid (Intermediate 69) (120 mg, 0.50 mmol) was added HATU (228 mg, 0.599 mmol)) and N,N-diisopropylethylamine (0.17 mL, 1.0 mmol). After 5 minutes, tert-butyl 3-aminoazetidine-1-carboxylate (103 mg, 0.599 mmol) was added, and the mixture was stirred for 2 h, diluted with water and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 20%-60% EtOAc/EtOH (3/1)-hexanes gradient to give the title compound as a white foam (171 mg, 87%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.42 (s, 9H), 2.48-2.52 (m, 2H), 2.69-2.73 (m, 2H), 2.95-3.05 (m, 1H), 3.72 (dd, J=9, 5 Hz, 2H), 3.82 (s, 3H), 4.25 (t, J=8 Hz, 2H), 4.59-4.68 (m, 1H), 4.91 (t, J=7 Hz, 1H), 6.25-6.31 (m, 1H), 6.46 (d, J=10 Hz, 1H), 6.55-6.62 (m, 1H), 6.77 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) M+H=395.

B. (trans)-N-(Azetidin-3-yl)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamide, trifluoroacetic acid salt

To a stirred solution of tert-butyl 3-((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)azetidine-1-carboxylate (Intermediate 71A) (171 mg, 0.434 mmol) in DCM (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol). After 1 h, the solvent was removed in vacuo and triturated with ether to afford the title compound as a white solid (181 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.36-2.51 (m, 2H), 2.60-2.75 (m, 2H), 3.07-3.18 (m, 1H), 3.81 (s, 3H), 4.14-4.22 (m, 2H), 4.24-4.34 (m, 2H), 4.61-4.69 (m, 1H), 4.80-4.89 (m, 1H), 6.55 (dd, J=10, 3 Hz, 1H), 6.61 (d, J=3 Hz, 1H), 6.92 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) M+H=295.

Intermediate 72: 2-(6-Amino-2-azaspiro[3.3]heptan-2-yl)isonicotinonitrile, di-trifluoroacetic acid salt

A. tert-Butyl (2-(4-cyanopyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)carbamate

To a DMF (3 mL) solution of tert-butyl 2-azaspiro[3.3]heptan-6-ylcarbamate (212 mg, 1.00 mmol) and 2-fluoroisonicotinonitrile (183 mg, 1.50 mmol) was added N,N-diisopropylethylamine (0.35 mL, 2.0 mmol). The mixture was heated to 100° C. for 3 h, cooled, diluted with water and extracted with EtOAc. The organic extracts were washed with water, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 20%-60% EtOAc/EtOH (3/1)-hexanes gradient to give the title compound as a white solid (245 mg, 78%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.44 (s, 9H), 2.04-2.14 (m, 2H), 2.59-2.67 (m, 2H), 3.97 (s, 2H), 4.04-4.11 (m, 1H), 4.07 (s, 2H), 4.61-4.71 (m, 1H), 6.41 (s, 1H), 6.72 (dd, J=5, 1 Hz, 1H), 8.22 (d, J=5 Hz, 1H); LC-MS (LC-ES) M+H=315.

B. 2-(6-Amino-2-azaspiro[3.3]heptan-2-yl)isonicotinonitrile, di-trifluoroacetic acid salt

To a stirred solution of tert-butyl (2-(4-cyanopyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)carbamate (Intermediate 72A) (245 mg, 0.779 mmol) in DCM (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol). After 1 h, the solvent was removed in vacuo and triturated with ether to afford the title compound as a pale yellow solid (413 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.38-2.46 (m, 2H), 2.68-2.75 (m, 2H), 3.71-3.80 (m, 1H), 4.17 (s, 2H), 4.26 (s, 2H), 6.93-6.96 (m, 1H), 6.98 (t, J=1 Hz, 1H), 8.12 (dd, J=6, 1 Hz, 1H); LC-MS (LC-ES) M+H=215.

Intermediate 73: 4-((trans)-4-Aminocyclohexyl)morpholin-3-one

A. Benzyl ((trans)-4-(2-(2-chloroethoxy)acetamido)cyclohexyl)carbamate

To a THF solution (30 mL) of 2-(2-chloroethoxy)acetyl chloride (958 mg, 6.11 mmol) and benzyl ((trans)-4-aminocyclohexyl)carbamate (1.38 g, 5.55 mmol) was added triethylamine (1.12 g, 11.1 mmol) at room temperature. After stirring overnight, the organics were taken up in CHCl 3 , washed with water, dried over MgSO 4 and concentrated to give the title compound as a light yellow solid (1.90 g, 93%) which was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.18-1.38 (m, 4H), 1.71-1.84 (m, 4H), 3.20-3.32 (m, 1H), 3.49-3.58 (m, 1H), 3.70-3.74 (m, 2H), 3.77-3.81 (m, 2H), 3.90 (s, 2H), 5.00 (s, 2H), 7.28-7.40 (m, 5H); LC-MS (LC-ES) M+H=369.

B. Benzyl ((trans)-4-(3-oxomorpholino)cyclohexyl)carbamate

An acetonitrile solution (60 mL) containing benzyl ((trans)-4-(2-(2-chloroethoxy)acetamido)cyclohexyl)carbamate (Intermediate 73A) (1.88 g, 5.10 mmol) and cesium carbonate (2.49 g, 7.65 mmol) was heated to reflux. After stirring overnight, the reaction was cooled, the solvent was removed in vacuo and the residual solid taken up in CHCl 3 followed by careful quenching with saturated aqueous NaHSO 4 . The organic layer was separated and the aqueous layer extracted with CHCl 3 . The combined organic layers were dried over MgSO 4 and concentrated, and the residue was purified on silica gel eluting with a 0%-15% MeOH-DCM gradient to give the title compound as a light yellow solid (1.37 g, 81%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.31-1.22 (m, 2H), 1.48-1.62 (m, 4H), 1.82-1.91 (m, 2H), 3.20-3.26 (m, 2H), 3.26-3.32 (m, 1H), 3.76-3.82 (m, 2H), 4.01 (s, 2H), 4.12-4.22 (m. 1H), 5.01 (s, 2H), 7.27-7.39 (m, 5H); LC-MS (LC-ES) M+H=333.

C. 4-((trans)-4-Aminocyclohexyl)morpholin-3-one

To a stirred solution of benzyl ((trans)-4-(3-oxomorpholino)cyclohexyl)carbamate (Intermediate 73B) (1.35 g, 4.06 mmol) in methanol (15 mL) under a nitrogen atmosphere was added 10% Pd/C (864 mg, 0.812 mmol). The reaction vessel was evacuated under reduced pressure and purged with hydrogen three times. The mixture was placed under a nitrogen atmosphere, fitted with a hydrogen filled balloon and stirred overnight under a hydrogen atmosphere. The mixture was filtered through a pad of Celite®, washing with DCM. The filtrate was evaporated to dryness to give the crude title compound (790 mg, 98%) as a waxy solid, which was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.04-1.16 (m, 2H), 1.45-1.57 (m, 4H), 1.76-1.85 (m, 2H), 2.42-2.53 (m, 1H), 3.20-3.26 (m, 2H), 3.76-3.81 (m, 2H), 4.00 (s, 2H), 4.13-4.22 (m, 1H).

Intermediate 74: (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(piperidin-4-yl)cyclobutanecarboxamide hydrochloride

A. tert-Butyl 4-((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)piperidine-1-carboxylate

To a DMF (10 mL) solution of (trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid (Intermediate 69) (300 mg, 1.25 mmol) was added HATU (570 mg, 1.50 mmol)) and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol). After 5 minutes, tert-butyl 4-aminopiperidine-1-carboxylate (300 mg, 1.50 mmol) was added, and the mixture was stirred for 2 h, diluted with water and MeOH, and loaded onto a semi-prep HPLC (NH 4 OH as modifier) to afford the title compound as a pale yellow foamy solid (370 mg, 70%). 1 H NMR (400 MHz, CDCl 3 ) δ 1.21-1.33 (m, 2H), 1.45 (s, 9H), 1.87-1.95 (m, 2H), 2.43-2.55 (m, 2H), 2.68-2.75 (m, 2H), 2.81-2.90 (m, 2H), 2.90-2.99 (m, 1H), 3.84 (s, 3H), 3.88-3.99 (m, 1H), 3.99-4.14 (m, 2H), 4.88-4.99 (m, 1H), 5.29-5.33 (m, 1H), 6.47 (dd, J=10, 3 Hz, 1H), 6.56-6.62 (m, 1H), 6.78 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) M+H=423.

B. (trans)-3-(5-Fluoro-2-methoxyphenoxy)-N-(piperidin-4-yl)cyclobutanecarboxamide hydrochloride

To a stirred solution of tert-butyl 4-((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)piperidine-1-carboxylate (Intermediate 74A) (370 mg, 0.876 mmol) in DCM (1.5 mL) was added 4 N HCl in dioxane (1.5 mL, 6.0 mmol). After 15 min, a small amount of MeOH was added to facilitate solubility. After 15 min, the solvent was removed in vacuo to afford the title compound as a white foamy solid (335 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.58-1.69 (m, 2H), 2.04-2.14 (m, 2H), 2.32-2.45 (m, 2H), 2.56-2.67 (m, 2H), 3.06-3.11 (m, 3H), 3.33-3.45 (m, 2H), 3.78 (s, 3H), 3.89-3.99 (m, 1H), 4.83-4.92 (m, 1H), 6.51-6.61 (m, 2H), 6.84-6.93 (m, 1H); LC-MS (LC-ES) M+H=323.

Intermediate 75: 2-((trans)-3-(5-Fluoro-2-methoxyphenoxy)cyclobutanecarboxamido)oxazole-4-carboxylic acid

To a DMF (12 mL) solution of (trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid (Intermediate 69) (340 mg, 1.42 mmol) was added HATU (646 mg, 1.70 mmol) and N,N-diisopropylethylamine (0.49 mL, 2.8 mmol). After 20 minutes, 2-aminooxazole-4-carboxylic acid (272 mg, 2.12 mmol) was added, and the mixture was stirred for 2 h, diluted with water and MeOH, and loaded onto a semi-prep HPLC (TFA as modifier) to afford the title compound as a pale yellow foamy solid (370 mg, 70%). 1 H NMR (400 MHz, CD 3 OD) δ 2.45-2.55 (m, 2H), 2.75-2.84 (m, 2H), 3.35-3.45 (m, 1H), 3.82 (s, 3H), 4.85-4.92 (m, 1H), 6.55-6.65 (m, 2H), 6.89-6.95 (m, 1H), 8.25 (s, 1H); LC-MS (LC-ES) M+H=351.

Intermediate 76: Racemic trans-N1-(1,1,1-Trifluoropropan-2-yl)cyclohexane-1,4-diamine dihydrochloride

A. Racemic tert-Butyl (trans-4-((1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)carbamate

N,N-Diisopropylethylamine (1.64 mL, 9.43 mmol) was added to tert-butyl (trans-4-aminocyclohexyl)carbamate (1.01 g, 4.71 mmol) in 1,4-dioxane (7.8 mL) at room temperature, followed by 1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate (1.39 g, 5.66 mmol), and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1:4) to give the title compound (906 mg, 59%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.98 (dq, J=11 Hz, 2H), 1.11 (dq, J=13, 3 Hz, 2H), 1.11 (d, J=7 Hz, 3H), 1.35 (s, 9H), 1.66-1.82 (m, 4H), 1.82-1.90 (m, 1H), 2.30-2.44 (m, 1H), 3.06-3.18 (m, 1H), 3.28 (h, J=7 Hz, 1H), 6.66 (d, J=8 Hz, 1H); LC-MS (LC-ES) M+H=311.

B. Racemic trans-N1-(1,1,1-Trifluoropropan-2-yl)cyclohexane-1,4-diamine dihydrochloride

4.0 M HCl in dioxane (7.3 mL, 29 mmol) was added to tert-butyl (trans-4-((1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)carbamate (Intermediate 76A) (0.91 g, 2.9 mmol) in MeOH (7.3 mL) at room temperature. After 15 h, the reaction mixture was concentrated to give the title compound (817 mg, 94%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.26-1.70 (m, 6H), 1.99 (br s, 3H), 2.14 (br s, 2H), 2.93 (br s, 1H), 3.15 (br s, 1H), 4.41 (br s, 1H), 8.08 (br s, 3H), 9.56 (br s, 1H), 10.25 (br s, 1H); LC-MS (LC-ES) M+H=211.

Intermediate 77: (trans)-3-(5-Fluoro-2-methoxyphenoxy)cyclobutanamine hydrochloride

A. tert-Butyl ((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutyl)carbamate

Triphenylphosphine (1.04 g, 3.96 mmol) was added to a solution of 5-fluoro-2-methoxyphenol (1.85 g, 10.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0° C., and tert-butyl ((cis)-3-hydroxycyclobutyl)carbamate (494 mg, 2.64 mmol) was added, followed by DIAD (0.77 mL, 4.0 mmol). The reaction mixture was then warmed to room temperature, stirred for 1 week, and partially concentrated. The remaining material was diluted with water and EtOAc, partitioned, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 30%-80% EtOAc-hexanes gradient to give the title compound (601 mg, 73%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 2.34-2.46 (m, 2H), 2.63-2.70 (s, 2H), 3.85 (s, 3H), 4.25-4.34 (m, 1H), 4.70-4.87 (m, 2H), 6.41 (dd, J=10, 3 Hz, 1H), 6.60 (d, J=3 Hz, 1H), 6.80 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) M+H-Boc=212.

B. (trans)-3-(5-Fluoro-2-methoxyphenoxy)cyclobutanamine hydrochloride

4.0 M HCl in dioxane (6 mL, 24 mmol) was added to tert-butyl ((trans)-3-(5-fluoro-2-methoxyphenoxy)cyclobutyl)carbamate (Intermediate 77A) (602 mg, 1.93 mmol) in DCM (2 mL). After 1 h, the reaction mixture was concentrated to give the title compound (481 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.31 (t, J=6 Hz, 2H), 2.66 (dd, J=7, 6 Hz, 4H), 3.84 (s, 3H), 3.96-4.06 (m, 1H), 4.94-5.01 (m, 1H), 6.58 (dd, J=10, 3 Hz, 1H), 6.64-6.73 (m, 1H), 6.97 (dd, J=9, 5 Hz, 1H); LC-MS (LC-ES) M+H=212.

Intermediate 78: (trans)-4-(2-Hydroxypropan-2-yl)cyclohexanecarboxylic acid

To a solution of (trans)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.00 g, 26.9 mmol) in THF (120 mL) at −20° C. was added 3 M MeMgBr in ether (26.9 mL, 81 mmol), dropwise at such a rate that the internal temperature remained <−15° C. The mixture was slowly warmed to room temperature overnight and after 30 h was cooled to −20° C. An additional portion of MeMgBr (4.5 mL; 13.5 mmol) was added dropwise. The mixture was allowed to warm to room temperature overnight. After 40 h the mixture was cooled to 0° C. and slowly quenched by addition of 2 N aqueous HCl (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was dissolved in a minimal amount of Et 2 O, and the product was precipitated by addition of hexanes and collected by filtration to afford the title compound as a colorless solid (4.36 g, 88%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.91-1.04 (m, 8H), 1.08-1.17 (m, 1H), 1.23 (qd, J=13, 3 Hz, 2H), 1.81 (dd, J=13, 3 Hz, 2H), 1.87-1.97 (m, 2H), 2.01-2.11 (m, 1H), 4.01 (s, 1H), 11.95 (s, 1H).

Intermediate 79: (trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(quinolin-8-yloxy)cyclobutanecarboxylate

Triphenylphosphine (5.42 g, 20.7 mmol) was added to a solution of quinolin-8-ol (2.00 g, 13.8 mmol) in tetrahydrofuran (40 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (2.15 g, 16.5 mmol) was added, followed by DIAD (4.0 mL, 21 mmol). The reaction mixture was then warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organics were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 30%-70% EtOAc-hexanes gradient to give the title compound as a thick oil (2.4 g, 66%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.74-2.84 (m, 2H), 2.86-2.96 (m, 2H), 3.23-3.31 (m, 1H), 3.78 (s, 3H), 5.14-5.23 (m, 1H), 6.91 (dd, J=7, 2 Hz, 1H), 7.41-7.52 (m, 3H), 8.16 (dd, J=8, 2 Hz, 1H), 8.98 (dd, J=4, 2 Hz, 1H); LC-MS (LC-ES) M+H=258.

B. (trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(quinolin-8-yloxy)cyclobutanecarboxylate (Intermediate 79A) (2.35 g, 9.13 mmol) in THF (15 mL) was added a solution of LiOH (1.15 g, 27.4 mmol) in water (7.5 mL). After 3 h, the mixture was adjusted to pH=4 with aqueous citric acid, and the aqueous phase was extracted with EtOAc (3×). The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated. The resulting yellow solid was triturated with diethyl ether to give the title compound (1.70 g, 77%). 1 H NMR (400 MHz, CDCl 3 ) δ 2.80-2.89 (m, 2H), 2.94-3.05 (m, 2H), 3.41 (tt, J=10, 5 Hz, 1H), 5.14-5.19 (m, 1H), 6.92 (dd, J=8, 1 Hz, 1H), 7.34-7.57 (m, 3H), 8.21 (dd, J=8, 2 Hz, 1H), 9.14 (dd, J=4, 2 Hz, 1H); LC-MS (LC-ES) M+H=244.

Intermediate 80: 2-((trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxamido)oxazole-4-carboxylic acid

To a solution of ethyl 2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)oxazole-4-carboxylate (Example 171) (110 mg, 0.288 mmol) in THF (1.6 mL) was added a solution of LiOH (36 mg, 0.87 mmol) in water (0.80 mL). After 2 h, the reaction was concentrated and azeotroped with toluene (3×) to give the title compound as a pale yellow solid (50 mg, 49%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.40-2.50 (m, 2H), 2.71-2.81 (m, 2H), 3.10-3.20 (m, 1H), 5.03 (quin, J=6 Hz, 1H), 6.98 (dd, J=7, 2 Hz, 1H), 7.41-7.58 (m, 3H), 7.58-7.65 (m, 1H), 8.30 (dd, J=8, 2 Hz, 1H), 8.86 (dd, J=4, 2 Hz, 1H), 11.55-12.73 (br s, 1H); LC-MS (LC-ES) M+H=354.

Intermediate 81: 4-Cyclopropyloxazol-2-amine

A. 1-Cyclopropyl-2-hydroxyethanone

To neat 2-bromo-1-cyclopropylethanone (2 g, 12.3 mmol) was added 1 N aqueous NaOH (12.3 mL, 12.3 mmol). The mixture was stirred for 2 h and then extracted with EtOAc (5×). The organics were dried over MgSO 4 , filtered and concentrated to give 1-cyclopropyl-2-hydroxyethane (1.1 g, 90%) as a dark liquid, which was used without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 1.00-1.05 (m, 2H), 1.15-1.21 (m, 2H), 1.87 (tt, J=8, 5 Hz, 1H), 3.15 (s, 1H), 4.42 (d, J=5 Hz, 2H).

B. 4-Cyclopropyloxazol-2-amine

To a THF (2 mL) solution of 1-cyclopropyl-2-hydroxyethanone (450 mg, 4.49 mmol) and cyanamide (227 mg, 5.39 mmol) was added 2 M aqueous NaOH (2.92 mL, 5.84 mmol) dropwise. After stirring overnight, the mixture was partially concentrated, diluted with water, and extracted with EtOAc (5×) and chloroform (3×). The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was loaded onto a semi-prep HPLC (NH 4 OH as modifier) to afford the title compound as a white solid (92 mg, 16%). 1 H NMR (400 MHz, CDCl 3 ) δ 0.66-0.72 (m, 2H), 0.77-0.83 (m, 2H), 1.66 (tt, J=8, 5 Hz, 1H), 4.64 (br s, 2H), 6.92 (s, 1H); LC-MS (LC-ES) M+H=125.

Intermediate 82: 8-(Azetidin-3-yloxy)quinoline dihydrochioride

A. tert-Butyl 3-(quinolin-8-yloxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (249 mg, 0.991 mmol) and quinolin-8-ol (145 mg, 0.999 mmol) in DMF (5 mL) was added cesium carbonate (360 g, 1.11 mmol). The mixture was heated to 80° C. overnight, poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 0%-90% EtOAc-hexanes gradient to give the title compound (144 mg, 48%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.40 (s, 9H), 3.90-3.96 (m, 2H), 4.36-4.42 (m, 2H), 5.17-5.22 (m, 1H), 6.96 (d, J=8 Hz, 1H), 7.48 (t, J=6 Hz, 1H), 7.55-7.60 (m, 2H), 8.32-8.36 (m, 1H), 8.87-8.90 (m, 1H); LC-MS (LC-ES) M+H=301.

B. 8-(Azetidin-3-yloxy)quinoline dihydrochloride

To tert-butyl 3-(quinolin-8-yloxy)azetidine-1-carboxylate (Intermediate 82A) (142 mg, 0.473 mmol) in methanol (1 mL), was added 4 M HCl in dioxane (4 mL, 16 mmol). The mixture was stirred at room temperature for 5 h and the solvent was removed in vacuo. The residue was diluted with diethyl ether, and the resulting precipitate was collected by filtration to give the title compound as a white solid (118 mg, 91%). 1 H NMR (400 MHz, CD 3 OD) δ 4.43-4.47 (m, 2H), 4.67-4.74 (m, 2H), 5.51-5.57 (m, 1H), 7.44 (d, J=8 Hz, 1H), 7.87 (t, J=6 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.11-8.16 (m, 1H), 9.14-9.19 (m, 2H); LC-MS (LC-ES) M+H=201.

Intermediate 83: N-Methoxy-N-methyl-2-((trans)-3-(quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxamide

2-((trans)-3-(Quinolin-8-yloxy)cyclobutanecarboxamido)thiazole-4-carboxylic acid (Example 193) (97 mg, 0.26 mmol) was dissolved in DMF (5 mL) followed by the addition of N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and HATU (120 mg, 0.32 mmol). The reaction was stirred at room temperature for ca. 5 min, and N,O-dimethylhydroxylamine hydrochloride (38 mg, 0.39 mmol) was added. After 12 h, the reaction was quenched with water, extracted with EtOAc, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel, eluting with a 0%-100% EtOAc:EtOH (3:1)-hexanes gradient to give the title compound (34 mg, 31%). LC-MS (LC-ES) M+H=413.

Intermediate 84: 2-(2-Aminothiazol-5-yl)propan-2-ol

3 M methylmagnesium bromide in THF solution (1.17 mL, 3.52 mmol) was added to 1-(2-aminothiazol-5-yl)ethanone (0.10 g, 0.70 mmol) in THF (5 mL). After 3 h, the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and evaporated under reduced pressure to give the title compound (42 mg, 36%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.39 (s, 6H), 5.11 (s, 1H), 6.55-6.66 (m, 3H); LC-MS (LC-ES) M+H=159.

Intermediate 85: 5-(Prop-1-en-2-yl)thiazol-2-amine, trifluoroacetic acid salt

A. tert-Butyl (5-acetylthiazol-2-yl)carbamate

Boc-anhydride (0.86 mL, 3.7 mmol) was added to 1-(2-aminothiazol-5-yl)ethanone (0.50 g, 3.5 mmol), N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and DMAP (4 mg, 0.04 mmol) in THF (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was concentrated, and the residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (409 mg, 48%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.47 (s, 9H), 2.44 (s, 3H), 8.22 (s, 1H), 11.95 (s, 1H); LC-MS (LC-ES) M−H=241.

B. tert-Butyl (5-(2-hydroxypropan-2-yl)thiazol-2-yl)carbamate

3 M methylmagnesium bromide in THF (0.55 mL, 1.7 mmol) was added to tert-butyl (5-acetylthiazol-2-yl)carbamate (Intermediate 85A) (0.20 g, 0.83 mmol) in THF (5 mL). After 3 h, the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and evaporated under reduced pressure. The residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (150 mg, 68%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.44 (s, 15H), 3.29 (s, 1H), 5.34 (s, 1H), 7.05 (s, 1H); LC-MS (LC-ES) M−H=257.

C. 5-(Prop-1-en-2-yl)thiazol-2-amine, trifluoroacetic acid salt

Trifluoroacetic acid (0.46 mL, 6.0 mmol) was added to a solution of tert-butyl (5-(2-hydroxypropan-2-yl)thiazol-2-yl)carbamate (Intermediate 85B) (155 mg, 0.600 mmol) in DCM (5 mL) cooled at 0° C. The reaction was allowed to warm to room temperature overnight and was concentrated. The resulting residue was triturated with hexanes to give the title compound (80 mg, 36%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.98 (s, 3H), 4.96 (d, J=11 Hz, 2H), 7.20 (br s, 1H); LC-MS (LC-ES) M+H=141.

Intermediate 86: 1-(2-Aminothiazol-4-yl)-2-methylpropan-2-ol hydrochloride

A. Methyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetate

Boc-anhydride (1.53 mL, 6.6 mmol) was added to methyl 2-(2-aminothiazol-4-yl)acetate (1.08 g, 6.28 mmol), N,N-diisopropylethylamine (1.21 mL, 6.91 mmol) and DMAP (8 mg, 0.06 mmol) in THF (20 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight, then heated to 90° C. After 2 h the reaction was concentrated, and the residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (1.35 g, 79%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.44 (s, 9H), 1.96 (s, 2H), 3.62 (s, 3H), 6.89 (s, 1H), 11.39 (s, 1H); LC-MS (LC-ES) M−H=271.

B. tert-Butyl (4-(2-hydroxy-2-methylpropyl)thiazol-2-yl)carbamate

3 M Methylmagnesium bromide in THF (0.98 mL, 2.9 mmol) was added to methyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetate (Intermediate 86A) (0.20 g, 0.73 mmol) in THF (5 mL). After 1 h, the reaction mixture was concentrated, and the residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (159 mg, 73%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.04 (s, 6H), 1.44 (s, 9H), 3.57 (s, 2H), 6.89 (s, 1H), 11.38 (s, 1H); LC-MS (LC-ES) M−H=271.

C. 1-(2-Aminothiazol-4-yl)-2-methylpropan-2-ol hydrochloride

To tert-butyl (4-(2-hydroxy-2-methylpropyhthiazol-2-yl)carbamate (Intermediate 86B) (159 mg, 0.582 mmol) in DCM (2 mL), was added 4 M HCl in dioxane (0.29 mL, 1.2 mmol). The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (120 mg, 99%). 1 H NMR (400 MHz, CD 3 OD) δ 1.10 (s, 6H), 3.63 (s, 2H), 6.66 (s, 1H), 9.31 (br s, 2H); LC-MS (LC-ES) M+H=173.

Intermediate 87: 1-(2-Aminothiazol-5-yl)-2-methylpropan-2-ol

A. Ethyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-5-yl)acetate

Boc-anhydride (1.18 mL, 5.07 mmol) was added to ethyl 2-(2-aminothiazol-5-yl)acetate (900 mg, 4.83 mmol), N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) and DMAP (6 mg, 0.05 mmol) in THF (20 mL) at 0° C. The reaction mixture was warmed to room temperature. After 2 h the reaction was concentrated, and the residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (1.01 g, 72%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.17 (t, J=7 Hz, 3H), 1.45 (s, 9H), 1.52 (s, 2H), 4.07 (q, J=7 Hz, 2H), 7.13 (s, 1H), 11.26 (br s, 1H); LC-MS (LC-ES) M−H=285.

B. tert-Butyl (5-(2-hydroxy-2-methylpropyl)thiazol-2-yl)carbamate

3 M Methylmagnesium bromide in THF (2.33 mL, 6.98 mmol) was added to ethyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-5-yl)acetate (Intermediate 87A) (0.20 g, 0.70 mmol) in THF (5 mL). After 1 h, the reaction mixture was concentrated, and the residue was purified on silica gel, eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (159 mg, 73%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.05 (s, 6H), 1.44 (s, 9H), 2.71 (s, 2H), 4.49 (s, 1H), 6.98 (s, 1H), 11.08 (br s, 1H); LC-MS (LC-ES) peak at T=0.65 min.

C. 1-(2-Aminothiazol-5-yl)-2-methylpropan-2-ol

Trifluoroacetic acid (0.36 mL, 4.7 mmol) was added to a solution of tert-butyl (5-(2-hydroxy-2-methylpropyl)thiazol-2-yl)carbamate (Intermediate 87B) (0.128 g, 0.470 mmol) in DCM (5 mL) cooled at 0° C. The reaction mixture was warmed to room temperature. After stirring overnight, the solvent was removed, and the residue was basified to pH=9 by adding saturated aqueous NaHCO 3 . The aqueous phase was extracted with ethyl acetate (3×), and the combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated to give the title compound (21 mg, 26%). 1 H NMR (400 MHz, CD 3 OD) δ 1.04 (s, 6H), 2.57 (s, 2H), 4.35 (s, 1H), 6.53 (s, 2H), 6.56 (s, 1H); LC-MS (LC-ES) M+H=173.

Intermediate 88: (trans)-3-(Quinolin-8-ylamino)cyclobutanecarboxylic acid

A. 4-Methyl-N-(quinolin-8-yl)benzenesulfonamide

A solution of quinolin-8-amine (1.00 g, 6.94 mmol) and tosyl chloride (1.98 g, 10.4 mmol) in pyridine (15 mL) was heated in a microwave at 130° C. for 10 min. The reaction mixture was poured into water (100 mL), and the solid was collected and dried via vacuum filtration to give the title compound (1.88 g, 90%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.23 (m, 3H), 7.25 (d, J=12 Hz, 2H), 7.45-7.49 (m, 1H), 7.53-7.58 (m, 1H), 7.59-7.67 (m, 2H), 7.77 (d, J=12 Hz, 2H), 8.32 (d, J=12 Hz, 1H), 8.81-8.86 (m, 1H), 9.84 (br s, 1H); LC-MS (LC-ES) M−H=299.

B. (trans)-Methyl 3-(4-methyl-N-(quinolin-8-yl)phenyl)sulfonamido)cyclobutanecarboxylate

Triphenylphosphine (0.948 g, 3.61 mmol) was added to a solution of 4-methyl-N-(quinolin-8-yl)benzenesulfonamide (Intermediate 88A) (1.08 g, 3.61 mmol) in tetrahydrofuran (30 mL). The reaction mixture was cooled to 0° C., and methyl 3-hydroxycyclobutanecarboxylate (0.35 mL, 3.0 mmol) was added, followed by DIAD (0.70 mL, 3.6 mmol). The reaction mixture was then warmed to room temperature, stirred overnight, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organics were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (0.691 g, 56%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.79-1.93 (m, 1H), 2.04 (dt, J=8, 4 Hz, 1H), 2.25-2.36 (m, 1H), 2.36-2.46 (m, 4H), 2.66-2.76 (m, 1H), 3.60 (s, 3H), 4.97 (t, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 2H), 7.49-7.59 (m, 4H), 7.65 (t, J=8 Hz, 1H), 8.06 (dd, J=8, 1 Hz, 1H), 8.41 (dd, J=8, 1 Hz, 1H), 8.71 (dd, J=4, 2 Hz, 1H); LC-MS (LC-ES) M+H=411.

C. (trans)-3-(4-Methyl-N-(quinolin-8-yl)phenyl)sulfonamido)cyclobutanecarboxylic acid

Lithium hydroxide (403 mg, 16.8 mmol) in water (5 mL) was added to a solution of (trans)-methyl 3-(4-methyl-N-(quinolin-8-yl)phenylsulfonamido)cyclobutanecarboxylate (Intermediate 88B) (690 mg, 1.68 mmol) in THF (15 mL). After 3 h, the reaction mixture was adjusted to pH 4 using saturated aqueous citric acid, and the aqueous phase was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 and evaporated to give the title compound (666 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.11-1.16 (m, 1H), 1.69-1.74 (m, 1H), 1.74-1.82 (m, 1H), 1.91-1.98 (m, 1H), 2.18-2.24 (m, 1H), 2.32 (s, 3H), 4.83-4.92 (m, 1H), 7.27 (d, J=8 Hz, 2H), 7.45-7.53 (m, 4H), 7.61 (t, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 8.38 (d, J=8 Hz, 1H), 8.65-8.69 (m, 1H); LC-MS (LC-ES) M+H=397.

D. (trans)-3-(Quinolin-8-ylamino)cyclobutanecarboxylic acid

A solution of (trans)-3-(4-methyl-N-(quinolin-8-yl)phenylsulfonamido)cyclobutanecarboxylic acid (Intermediate 88C) (666 mg, 1.68 mmol) in concentrated aqueous H 2 SO 4 (0.38 mL, 71 mmol) was stirred at 110° C. After 2 h, the reaction mixture was adjusted to neutral pH using 1 M aqueous NaOH, and the aqueous phase was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , and evaporated to give the title compound (326 mg, 80%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.24-2.34 (m, 2H), 2.60-2.69 (m, 2H), 3.02-3.11 (m, 1H), 4.12-4.22 (m, 1H), 6.50-6.53 (m, 1H), 6.58-6.62 (m, 1H), 7.06-7.11 (m, 1H), 7.32-7.36 (m, 1H), 7.48-7.54 (m, 1H), 8.19-8.24 (m, 1H), 8.72-8.77 (m, 1H), 12.03 (br s, 1H); LC-MS (LC-ES) M+H=243.

Intermediate 89: tert-Butyl 3-(thieno[3,2-b]pyridin-3-yloxy)azetidine-1-carboxylate

A. Methyl 3-hydroxythieno[3,2-b]pyridine-2-carboxylate

To methyl 3-chloropicolinate (1.0 g, 5.8 mmol) and sodium tert-butoxide (1.23 g, 12.8 mmol) in DMF (12 ml) was added methyl thioglycolate (0.62 ml, 7.0 mmol), and this mixture was heated to 65° C. overnight. The reaction was allowed to cool, and the mixture was stirred vigorously and diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound as a yellow solid (55 mg, 9%). 1 H NMR (400 MHz, CD 3 OD) δ 3.82 (s, 3H), 7.32 (dd, J=8, 4 Hz, 1H), 8.06 (d, J=8 Hz, 1H), 8.51 (d, J=4 Hz, 1H); LC-MS (LC-ES) M+H=210.

B. tert-Butyl 3-(thieno[3,2-b]pyridin-3-yloxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (107 mg, 0.426 mmol) and methyl 3-hydroxythieno[3,2-b]pyridine-2-carboxylate (Intermediate 89A) (75 mg, 0.36 mmol) in DMF (0.8 mL) was added cesium carbonate (140 g, 0.430 mmol). The mixture was heated to 110° C. overnight, poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 30%-90% EtOAc-heptane gradient to give material that was further purified on reverse-phase silica gel, eluting with a 5%-95% acetonitrile-water (TFA additive) gradient. The appropriate fractions were concentrated, and the resulting material was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate, filtered and concentrated to give the title compound (50 mg, 46%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 4.14-4.23 (m, 2H), 4.38 (dd, J=10, 7 Hz, 2H), 5.01-5.12 (m, 1H), 6.67 (s, 1H), 7.59 (dd, J=8, 5 Hz, 1H), 8.42 (d, J=8 Hz, 1H), 8.90 (d, J=5 Hz, 1H); LC-MS (LC-ES) M+H=307.

Intermediate 90: (trans)-3-((5-Fluorobenzofuran-7-yl)oxy)cyclobutanecarboxylic acid

A. 2-(5-Fluorobenzofuran-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

7-Bromo-5-fluorobenzofuran (0.25 g, 1.16 mmol), bis(pinacolato)diboron (0.354 g, 1.40 mmol), potassium acetate (0.285 g, 2.91 mmol), and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.095 g, 0.12 mmol) were stirred in DMSO (3.0 ml). The reaction solution was degassed and flushed with nitrogen and heated to 85° C. After 5 h, the reaction was allowed to cool overnight, and was diluted with ethyl acetate and washed with water and brine. The organic layers were dried over sodium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography eluting with a 10%-60% ethyl acetate in heptanes gradient to give the title compound (237 mg, 78%) as a white crystalline solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.41 (s, 12H), 6.73 (d, J=2 Hz, 1H), 7.31-7.35 (m, 1H), 7.45 (dd, J=9, 3 Hz, 1H), 7.76 (d, J=2 Hz, 1H); LC-MS (LC-ES) M−H=263.

B. 5-Fluorobenzofuran-7-ol

To 2-(5-fluorobenzofuran-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 90A) (0.23 g, 0.88 mmol) in ethanol (1.0 ml) at 0° C. was added 30% H 2 O 2 in water (0.1 ml, 1 mmol). After 2 h, the reaction was quenched with 10% aqueous Na 2 S 2 O 3 , diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (86 mg, 64%) as an oil which was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 6.55 (dd, J=11, 3 Hz, 1H), 6.85 (dd, J=9, 2 Hz, 1H), 6.88 (d, J=2 Hz, 1H), 7.98 (d, J=2 Hz, 1H), 10.52 (s, 1H); LC-MS (LC-ES) M+H=153.

C. (trans)-Methyl 3-((5-fluorobenzofuran-7-yl)oxy)cyclobutanecarboxylate

Triphenylphosphine (161 mg, 0.615 mmol) was added to a solution of 5-fluorobenzofuran-7-ol (Intermediate 90B) (85 mg, 0.56 mmol) in tetrahydrofuran (0.6 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (87 mg, 0.67 mmol) was added, followed by DIAD (0.12 mL, 0.62 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 5 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 10%-50% EtOAc-heptane gradient to give the title compound (71 mg, 48%). 1 H NMR (400 MHz, CDCl 3 ) δ 2.54-2.67 (m, 2H), 2.81 (qd, J=7, 4 Hz, 2H), 3.19-3.28 (m, 1H), 3.75 (s, 3H), 5.02-5.10 (m, 1H), 6.41 (dd, J=11, 2 Hz, 1H), 6.72 (d, J=1 Hz, 1H), 6.85 (dd, J=8, 2 Hz, 1H), 7.63 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=265.

D. (trans)-3-((5-Fluorobenzofuran-7-yl)oxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-((5-fluorobenzofuran-7-yl)oxy)cyclobutanecarboxylate (Intermediate 90C) (70 mg, 0.27 mmol) in THF (2 mL) was added a solution of LiOH (17 mg, 0.40 mmol) in water (0.5 mL). After stirring overnight, the reaction was concentrated. The residue was treated with 1 N aqueous HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (72 mg, quantitative) as a white solid. LC-MS (LC-ES) M−H=249.

Intermediate 91: (trans)-Methyl 3-(3-bromophenoxy)cyclobutanecarboxylate

Triphenylphosphine (364 mg, 1.39 mmol) was added to a solution of 3-bromophenol (200 mg, 1.16 mmol) in tetrahydrofuran (1.2 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (181 mg, 1.39 mmol) was added, followed by DIAD (0.25 mL, 1.3 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 10%-60% EtOAc-heptane gradient to give the title compound (265 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ) δ 2.40-2.51 (m, 2H), 2.74 (ddd, J=14, 7, 4 Hz, 2H), 3.14-3.25 (m, 1H), 3.75 (s, 3H), 4.88 (quin, J=7 Hz, 1H), 6.73 (d, J=7 Hz, 1H), 6.95 (s, 1H), 7.05-7.18 (m, 2H); LC-MS (LC-ES) M+H=285, 287 (Br pattern).

Intermediate 92: (trans)-3-(2,5-Difluorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(2,5-difluorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (484 mg, 1.85 mmol) was added to a solution of 2,5-difluorophenol (0.2 g, 1.537 mmol) in tetrahydrofuran (1.7 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (240 mg, 1.85 mmol) was added, followed by DIAD (0.35 mL, 1.8 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 10%-60% EtOAc-heptane gradient to give the title compound (236 mg, 63%). 1 H NMR (400 MHz, CDCl 3 ) δ 2.48-2.59 (m, 2H), 2.76 (ddd, J=14, 7, 4 Hz, 2H), 3.16-3.26 (m, 1H), 3.75 (s, 3H), 4.90 (quin, J=7 Hz, 1H), 6.49-6.63 (m, 2H), 7.02 (ddd, J=10, 9, 5 Hz, 1H); LC-MS (LC-ES) M+H=243.

B. (trans)-3-(2,5-Difluorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2,5-difluorophenoxy)cyclobutanecarboxylate (Intermediate 92A) (230 mg, 0.950 mmol) in THF (4 mL), methanol (2 mL) and water (2 mL) was added LiOH (68 mg, 2.85 mmol). After stirring overnight, the reaction was concentrated. The residue was taken up in water and treated with 6 N aqueous HCl until a precipitate began to form. This solid was collected by filtration and dried under vacuum to give the title compound (185 mg, 85%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.29-2.40 (m, 2H), 2.68 (qd, J=7, 5 Hz, 2H), 3.05-3.15 (m, 1H), 4.89 (quin, J=7 Hz, 1H), 6.70-6.80 (m, 1H), 6.86 (ddd, J=10, 7, 3 Hz, 1H), 7.26 (ddd, J=11, 9, 6 Hz, 1H), 12.34 (s, 1H); LC-MS (LC-ES) M−H=227.

Intermediate 93: Lithium (trans)-3-(2-chloro-5-fluorophenoxy)cyclobutanecarboxylate

A. (trans)-Methyl 3-(2-chloro-5-fluorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (430 mg, 1.64 mmol) was added to a solution of 2-chloro-5-fluorophenol (200 mg, 1.37 mmol) in tetrahydrofuran (2 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (213 mg, 1.64 mmol) was added, followed by DIAD (0.32 mL, 1.6 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 10%-50% EtOAc-heptane gradient to give the title compound (264 mg, 64%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 2.50-2.61 (m, 2H), 2.78 (ddd, J=14, 7, 4 Hz, 2H), 3.18-3.28 (m, 1H), 3.76 (s, 3H), 4.91 (quin, J=7 Hz, 1H), 6.49 (dd, J=10, 3 Hz, 1H), 6.63 (td, J=8, 3 Hz, 1H), 7.30 (dd, J=9, 6 Hz, 1H); LC-MS (LC-ES) M+H=259, 261 (CI pattern).

B. Lithium (trans)-3-(2-chloro-5-fluorophenoxy)cyclobutanecarboxylate

To a solution of (trans)-methyl 3-(2-chloro-5-fluorophenoxy)cyclobutanecarboxylate (Intermediate 93A) (245 mg, 0.947 mmol) in THF (4 mL), methanol (2 mL) and water (2 mL) was added LiOH (68 mg, 2.84 mmol). After stirring overnight, the reaction was concentrated to give the title compound (248 mg, quantitative) as a white solid that was used crude. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.03-2.15 (m, 2H), 2.53-2.66 (m, 3H), 4.81-4.92 (m, 1H), 6.69 (d, J=11 Hz, 1H), 6.80 (td, J=8, 3 Hz, 1H), 7.45 (dd, J=9, 6 Hz, 1H); LC-MS (LC-ES) M−H=243, 245 (CI pattern).

Intermediate 94: 1-(5-Methylpyridin-2-yl)azetidin-3-amine

A. Benzyl (1-(5-methylpyridin-2-yl)azetidin-3-yl)carbamate

To benzyl azetidin-3-ylcarbamate (1.24 g, 6.00 mmol) and 2-chloro-5-methylpyridine (638 mg, 5.00 mmol) in toluene (8 mL) was added sodium tert-butoxide (577 mg, 6.00 mmol) followed by BINAP (78 mg, 0.13 mmol) and Pd 2 (dba) 3 (73 mg, 0.080 mmol). The resulting mixture was heated to 70° C. overnight. The reaction was allowed to cool, ether was added and the mixture was washed with brine (3×). The washing was extracted with ether, and the organics were combined and dried over MgSO 4 , filtered, concentrated and purified on silica gel, eluting with 20% to 85% EtOAc in hexanes to afford the title compound (640 mg, 43%), a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 2.21 (s, 3H), 3.79 (dd, J=8, 6 Hz, 2H), 4.35 (t, J=8 Hz, 2H), 4.70 (d, J=7 Hz, 1H), 5.14 (s, 2H), 5.25 (d, J=8 Hz, 1H), 6.28 (d, J=9 Hz, 1H), 7.29-7.42 (m, 6H), 7.91-8.00 (m, 1H); LC-MS (LC-ES) M+H=298.

B. 1-(5-Methylpyridin-2-yl)azetidin-3-amine

Palladium on carbon (379 mg, 0.356 mmol) was added to benzyl (1-(5-methylpyridin-2-yl)azetidin-3-yl)carbamate (Intermediate 94A) (0.530 g, 1.78 mmol) in EtOAc (5 mL) and MeOH (15 mL) under a nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon, and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for 6 h under a hydrogen atmosphere. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (417 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.30 (s, 3H), 4.29-4.41 (m, 3H), 4.60-4.69 (m, 2H), 6.88 (d, J=9 Hz, 1H), 7.84 (s, 1H), 7.90 (dd, J=9, 2 Hz, 1H); LC-MS (LC-ES) M+H=164.

Intermediate 95: 4-Nitrophenyl (1-(5-methylpyridin-2-yl)azetidin-3-yl)carbamate

To 4-nitrophenyl chloroformate (278 mg, 1.38 mmol) and 1-(5-methylpyridin-2-yl)azetidin-3-amine (Intermediate 94) (150 mg, 0.919 mmol) in DCM (5 mL) at 0° C. was added pyridine (0.11 mL, 1.4 mmol), and the mixture was allowed to warm to room temperature. After 3 h, the resulting solid was collected by filtration and washed with DCM and acetonitrile to give the title compound as a white solid (113 mg, 38%). 1 H NMR (400 MHz, CDCl 3 ) δ 2.22 (s, 3H), 4.74-4.79 (m, 4H), 4.81-4.91 (m, 1H), 6.53 (d, J=9 Hz, 1H), 7.34 (d, J=9 Hz, 2H), 7.61-7.69 (m, 1H), 7.77 (s, 1H), 7.92 (br s, 1H), 8.27 (d, J=9 Hz, 2H); LC-MS (LC-ES) M+H=329.

Intermediate 96: Racemic 1-(6-Aminospiro[3.3]heptan-2-yl)propan-1-one hydrochloride

A. Racemic tert-Butyl (6-(1-hydroxycyclopropyl)spiro[3.3]heptan-2-yl)carbamate

To a stirred solution of methyl 6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate (500 mg, 1.87 mmol) and titanium(IV) isopropoxide (0.11 mL, 0.37 mmol) in diethyl ether (7 mL) was added 3 M ethylmagnesium bromide in ether (1.86 mL, 5.57 mmol) over 30 min (using water bath to keep the temperature from rising). After 1 h, the reaction was poured into water, and 10% aqueous sulfuric acid solution was added at 0° C. until the mixture was clear. The mixture was extracted with EtOAc, and the combined organics were washed with water, brine, dried over MgSO 4 , filtered and then concentrated. The residue was purified on silica gel, eluting with 0% to 60% EtOAc in hexanes to afford the title compound (62 mg, 12%). 1 H NMR (400 MHz, CDCl 3 ) δ 0.40-0.50 (m, 2H), 0.66-0.75 (m, 2H), 1.45 (s, 9H), 1.70-1.97 (m, 6H), 2.02-2.13 (m, 1H), 2.18-2.42 (m, 2H), 2.44-2.56 (m, 1H), 4.00 (br s, 1H), 4.61 (br s, 1H.

B. Racemic 1-(6-Aminospiro[3.3]heptan-2-yl)propan-1-one hydrochloride

To tert-butyl (6-(1-hydroxycyclopropyl)spiro[3.3]heptan-2-yl)carbamate (Intermediate 96A) (62 mg, 0.23 mmol) in DCM (1 mL) at 0° C. was added 4 M HCl in dioxane (1 mL, 4 mmol). The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo at room temperature to give the title compound (56 mg, quantitative), which was used crude. 1 H NMR (400 MHz, CD 3 OD) δ 1.03 (t, J=7 Hz, 3H), 2.15-2.39 (m, 6H), 2.44 (q, J=7 Hz, 2H), 2.55 (ddd, J=12, 7, 5 Hz, 1H), 3.24-3.33 (m, 1H), 3.58-3.72 (m, 2H).

Intermediate 97: 6-(3-Aminoazetidin-1-yl)-N-(2-ethoxyethyl)pyridazine-3-carboxamide dihydrochloride

A. 6-Chloro-N-(2-ethoxyethyl)pyridazine-3-carboxamide

To a DMF (5 mL) solution of 6-chloropyridazine-3-carboxylic acid (430 mg, 2.71 mmol) and 2-ethoxyethanamine (508 mg, 5.70 mmol) was added, dropwise, a 50% solution of T3P in ethyl acetate (1.73 mL, 2.71 mmol). The mixture was stirred overnight, quenched with water for 10 min and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO 4 , filtered and then concentrated to give the title compound (536 mg, 86%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.17-1.30 (m, 3H), 3.57 (q, J=7 Hz, 2H), 3.61-3.68 (m, 2H), 3.70-3.79 (m, 2H), 7.71 (d, J=9 Hz, 1H), 8.30 (d, J=9 Hz, 1H), 8.37 (br s, 1H); LC-MS (LC-ES) M+H=230.

B. tert-Butyl (1-(6-((2-ethoxyethyl)carbamoyl)pyridazin-3-azetidin-3-yl)carbamate

To a reaction vial with tert-butyl azetidin-3-ylcarbamate hydrochloride (360 mg, 2.09 mmol) in acetonitrile (15 mL) was added 6-chloro-N-(2-ethoxyethyl)pyridazine-3-carboxamide (Intermediate 97A) (480 mg, 2.09 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.1 mmol). The mixture was heated at 105° C. overnight, cooled and concentrated. The resulting residue was purified on silica gel eluting with a 5%-25% MeOH in DCM gradient to give the title compound (535 mg, 70%) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.21 (t, J=7 Hz, 3H), 1.48 (s, 9H), 3.52-3.68 (m, 6H), 4.06 (dd, J=9, 6 Hz, 2H), 4.49 (t, J=8 Hz, 2H), 4.62 (d, J=6 Hz, 1H), 6.90 (d, J=9 Hz, 1H), 7.94 (d, J=9 Hz, 1H); LC-MS (LC-ES) M+H=366.

C. 6-(3-Aminoazetidin-1-yl)-N-(2-ethoxyethyl)pyridazine-3-carboxamide dihydrochloride

To tert-butyl (1-(6-((2-ethoxyethyl)carbamoyl)pyridazin-3-yl)azetidin-3-yl)carbamate (Intermediate 97B) (535 mg, 1.46 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give the title compound as a light tan solid (388 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.20 (t, J=7 Hz, 3H), 3.50-3.64 (m, 6H), 4.41-4.49 (m, 1H), 4.58 (ddd, J=11, 5, 1 Hz, 2H), 4.79-4.88 (m, 2H), 7.61 (d, J=10 Hz, 1H), 8.32 (d, J=10 Hz, 1H); LC-MS (LC-ES) M+H=266.

Intermediate 98: 1-(Pyrazin-2-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(pyrazin-2-yl)azetidin-3-yl)carbamate

To a reaction vial with tert-butyl azetidin-3-ylcarbamate hydrochloride (902 mg, 5.24 mmol) in acetonitrile (15 mL) was added 2-chloropyrazine (600 mg, 5.24 mmol) and N,N-diisopropylethylamine (1.37 mL, 7.86 mmol). The mixture was heated to 100° C. for 1 h, heated to 90° C. overnight, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 5%-20% MeOH in DCM gradient to give the title compound (595 mg, 45%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 3.94 (dd, J=8, 6 Hz, 2H), 4.38 (t, J=8 Hz, 2H), 4.58 (d, J=6 Hz, 1H), 7.83 (dd, J=11, 2 Hz, 2H), 8.03 (dd, J=3, 2 Hz, 1H); LC-MS (LC-ES) M+H=251.

B. 1-(Pyrazin-2-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(pyrazin-2-yl)azetidin-3-yl)carbamate (Intermediate 98A) (590 mg, 2.36 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature for 1.5 h, and the solvent was removed in vacuo to give the title compound as a yellow solid (574 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.30-4.48 (m, 3H), 4.61-4.79 (m, 2H), 8.03 (d, J=4 Hz, 1H), 8.31 (d, J=1 Hz, 1H), 8.50 (dd, J=4, 1 Hz, 1H); LC-MS (LC-ES) M+H=151.

Intermediate 99: Racemic 6-Fluoro-4-((2-methylazetidin-3-yl)oxy)benzo[d]thiazole hydrochloride

A. Racemic tert-Butyl 2-methyl-3-((methylsulfonyl)oxy)azetidine-1-carboxylate

To a stirred, cooled (0° C.) solution of tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (600 mg, 3.20 mmol) in DCM (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by methanesulfonyl chloride (0.30 mL, 3.9 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into 1 N aqueous HCl and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound (814 mg, 96%) as a pale yellow oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.32-1.43 (m, 12H), 3.26 (s, 3H), 3.80 (dd, J=9, 4 Hz, 1H), 4.11 (t, J=8 Hz, 1H), 4.20-4.29 (m, 1H), 4.84 (d, J=5 Hz, 1H).

B. Racemic tert-Butyl 3-((6-fluorobenzo[d]thiazol-4-yl)oxy)-2-methylazetidine-1-carboxylate

To a stirred solution of tert-butyl 2-methyl-3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 99A) (265 mg, 0.999 mmol) and 6-fluorobenzo[d]thiazol-4-ol (170 mg, 1.01 mmol) in DMF (5 mL) was added cesium carbonate (360 mg, 1.11 mmol). The mixture was heated to 100° C. overnight, then 120° C. overnight, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 0%-40% EtOAc-hexanes gradient to give the title compound (116 mg, 34%) as a yellow oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.29 (d, J=7 Hz, 3H), 1.41 (s, 9H), 3.85 (br s, 1H), 4.32 (br s, 1H), 4.70 (t, J=6 Hz, 1H), 5.28 (td, J=7, 4 Hz, 1H), 6.91 (dd, J=11, 2 Hz, 1H), 7.66 (dd, J=8, 2 Hz, 1H), 9.27 (s, 1H); LC-MS (LC-ES) M+H=339.

C. Racemic 6-Fluoro-4-((2-methylazetidin-3-yl)oxy)benzo[d]thiazole hydrochloride

To tert-butyl 3-((6-fluorobenzo[d]thiazol-4-yl)oxy)-2-methylazetidine-1-carboxylate (Intermediate 99B) (116 mg, 0.343 mmol) in MeOH (0.5 mL) was added 4 N HCl in dioxane (2 mL, 8.0 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give material that was triturated with diethyl ether to give the title compound as a pale yellow solid (93 mg, 99%). 1 H NMR (400 MHz, CD 3 OD) δ 1.46 (d, J=7 Hz, 3H), 3.97-4.04 (m, 1H), 4.45 (dd, J=12, 6 Hz, 1H), 4.89-5.02 (m, 1H), 5.30-5.43 (m, 1H), 7.03 (dd, J=11, 2 Hz, 1H), 7.72 (dd, J=8, 2 Hz, 1H), 9.20 (br s, 1H), 9.30 (s, 1H); LC-MS (LC-ES) M+H=239.

Intermediate 100: 3-Methyl-1-(pyridazin-3-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (3-methyl-1-(pyridazin-3-yl)azetidin-3-yl)carbamate

To tert-butyl (3-methylazetidin-3-yl)carbamate hydrochloride (737 mg, 3.31 mmol) in acetonitrile (15 mL) was added 3-chloropyridazine hydrochloride (500 mg, 3.31 mmol) and N,N-diisopropylethylamine (1.45 mL, 8.28 mmol). The mixture was heated to 100° C. overnight, cooled and concentrated. The resulting residue was purified on silica gel eluting with a 5%-30% MeOH in DCM gradient to give the title compound (331 mg, 38%) as a brown oil. 1 H NMR (400 MHz, CD 3 OD) δ 1.45 (s, 9H), 1.67 (s, 3H), 4.02 (d, J=8 Hz, 2H), 4.29 (d, J=8 Hz, 2H), 6.56 (dd, J=9, 1 Hz, 1H), 7.20 (dd, J=9, 5 Hz, 1H), 8.60 (dd, J=5, 1 Hz, 1H); LC-MS (LC-ES) M+H=265.

B. 3-Methyl-1-(pyridazin-3-yl)azetidin-3-amine dihydrochloride

To tert-butyl (3-methyl-1-(pyridazin-3-yl)azetidin-3-yl)carbamate (Intermediate 100A) (87 mg, 0.35 mmol) in DCM (1 mL) and MeOH (1 mL) was added 4 N HCl in dioxane (1.5 mL, 6.0 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo to give the title compound as a tan solid (84 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.78 (s, 3H), 4.41-4.50 (m, 2H), 4.53-4.63 (m, 2H), 7.63 (dd, J=9, 1 Hz, 1H), 7.96 (dd, J=9, 5 Hz, 1H), 8.65 (d, J=4 Hz, 1H); LC-MS (LC-ES) M+H=165.

Intermediate 101: 3-Methyl-1-(pyrimidin-2-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (3-methyl-1-(pyrimidin-2-yl)azetidin-3-yl)carbamate

To a stirred solution of 2-chloropyrimidine (500 mg, 4.37 mmol) in acetonitrile (15 mL) was added N,N-diisopropylethylamine (2.67 mL, 15.3 mmol) followed by tert-butyl (3-methylazetidin-3-yl)carbamate hydrochloride (972 mg, 4.37 mmol). The mixture was heated to 100° C. overnight, cooled and concentrated. The resulting residue was purified on silica gel eluting with a 0%-30% MeOH in DCM gradient to give the title compound (750 mg, 65%) as a yellowish oil. 1 H NMR (400 MHz, CDCl 3 ) δ 1.45 (s, 9H), 1.65 (s, 3H), 4.00 (d, J=9 Hz, 2H), 4.29 (d, J=8 Hz, 2H), 4.82 (br s, 1H), 6.56 (t, J=5 Hz, 1H), 8.33 (d, J=5, 1 Hz, 2H); LC-MS (LC-ES) M+H=265.

B. 3-Methyl-1-(pyrimidin-2-yl)azetidin-3-amine dihydrochloride

To tert-butyl (3-methyl-1-(pyrimidin-2-yl)azetidin-3-yl)carbamate (Intermediate 101A) (750 mg, 2.84 mmol) in DCM (1 mL) and MeOH (2 mL) was added 4 N HCl in dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo to give the title compound as a tan solid (720 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 1.77 (s, 3H), 4.38-4.48 (m, 2H), 4.51-4.60 (m, 2H), 7.06-7.12 (m, 1H), 8.68 (d, J=5 Hz, 2H); LC-MS (LC-ES) M+H=165.

Intermediate 102: Racemic 4-((2-Methylazetidin-3-yl)oxy)benzo[d]thiazole hydrochloride

A. Racemic tert-Butyl 3-(benzo[d]thiazol-4-yloxy)-2-methylazetidine-1-carboxylate

To a stirred solution of tert-butyl 2-methyl-3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 99A) (184 mg, 0.693 mmol) and benzo[d]thiazol-4-ol (105 mg, 0.693 mmol) in DMF (4 mL) was added cesium carbonate (250 mg, 0.767 mmol). The mixture was heated to 80° C. overnight, then 100° C. overnight, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient to give the title compound (103 mg, 46%) as a colorless oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.25-1.46 (m, 12H), 3.82-3.92 (m, 1H), 4.29 (br s, 1H), 4.84 (dt, J=7, 4 Hz, 1H), 5.27 (td, J=7, 4 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.35-7.44 (m, 1H), 7.71-7.79 (m, 1H), 9.30 (s, 1H); LC-MS (LC-ES) M+H=321.

B. Racemic 4-((2-Methylazetidin-3-yl)oxy)benzo[d]thiazole hydrochloride

To tert-butyl 3-(benzo[d]thiazol-4-yloxy)-2-methylazetidine-1-carboxylate (Intermediate 102A) (102 mg, 0.318 mmol) in MeOH (0.5 mL) was added 4 N HCl in dioxane (2 mL, 8.0 mmol). The mixture was stirred at room temperature for 2 h, and the solvent was removed in vacuo to give material that was triturated with diethyl ether to give the title compound as a white solid (85 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.43-1.55 (m, 3H), 3.93-4.09 (m, 1H), 4.35-4.45 (m, 1H), 4.85-4.99 (m, 1H), 5.30-5.44 (m, 1H), 6.99 (d, J=8 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 9.29 (br s, 1H), 9.34 (s, 1H); LC-MS (LC-ES) M+H=221.

Intermediate 103: 1-(5-Methylpyridazin-3-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(5-methylpyridazin-3-yl)azetidin-3-yl)carbamate

To a reaction vial with 3-chloro-5-methylpyridazine (600 mg, 4.67 mmol) dissolved in acetonitrile (15 mL) was added tert-butyl azetidin-3-ylcarbamate (804 mg, 4.67 mmol) and N,N-diisopropylethylamine (1.22 mL, 7.00 mmol). The mixture was heated to 100° C. overnight, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 5%-30% MeOH in DCM gradient to give the title compound (215 mg, 17%) as a tan solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 2.30 (s, 3H), 3.93 (dd, J=8, 6 Hz, 2H), 4.38 (t, J=8 Hz, 2H), 4.51-4.67 (m, 1H), 6.70 (s, 1H), 8.37 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=265.

B. 1-(5-Methylpyridazin-3-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(5-methylpyridazin-3-yl)azetidin-3-yl)carbamate (Intermediate 103A) (210 mg, 0.794 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (3 mL, 12 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo to give the title compound as a dark tan solid (206 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 2.50 (d, J=1 Hz, 3H), 4.37-4.50 (m, 3H), 4.68-4.79 (m, 2H), 7.43 (s, 1H), 8.51 (s, 1H); LC-MS (LC-ES) M+H=165.

Intermediate 104: 1-(Pyridazin-3-yl)azetidin-3-amine dihydrochloride

A. tert-Butyl (1-(pyridazin-3-yl)azetidin-3-yl)carbamate

To a reaction vial with 3-chloropyridazine hydrochloride (150 mg, 0.993 mmol) dissolved in EtOH (5 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) followed by tert-butyl azetidin-3-ylcarbamate (171 mg, 0.993 mmol). The mixture was heated to 90° C. overnight, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 5%-25% MeOH in DCM gradient to give the title compound (87 mg, 35%) as a tan solid. 1 H NMR (400 MHz, CD 3 OD) δ 1.47 (s, 9H), 3.96 (dd, J=8, 6 Hz, 2H), 4.40 (t, J=8 Hz, 2H), 4.53-4.70 (m, 1H), 6.87 (dd, J=9, 1 Hz, 1H), 7.41 (dd, J=9, 5 Hz, 1H), 8.49 (dd, J=5, 1 Hz, 1H); LC-MS (LC-ES) M+H=251.

B. 1-(Pyridazin-3-yl)azetidin-3-amine dihydrochloride

To tert-butyl (1-(pyridazin-3-yl)azetidin-3-yl)carbamate (Intermediate 104A) (87 mg, 0.35 mmol) in DCM (1 mL) and MeOH (1 mL) was added 4 N HCl in dioxane (1.5 mL, 6.0 mmol). The mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo to give the title compound as a tan solid (84 mg, quantitative). 1 H NMR (400 MHz, CD 3 OD) δ 4.38-4.54 (m, 3H), 4.72-4.82 (m, 2H), 7.63 (dd, J=9, 1 Hz, 1H), 7.95 (dd, J=9, 5 Hz, 1H), 8.63 (d, J=4 Hz, 1H); LC-MS (LC-ES) M+H=151.

Intermediate 105: 4-Nitrophenyl (3-methyl-1-(pyrimidin-2-yl)azetidin-3-yl)carbamate

To 4-nitrophenyl chloroformate (179 mg, 0.886 mmol) and 3-methyl-1-(pyrimidin-2-yl)azetidin-3-amine dihydrochloride (Intermediate 101) (150 mg, 0.633 mmol) in DCM (3 mL) at 0° C. was added, dropwise, pyridine (0.18 mL, 2.2 mmol) in DCM (5 mL). After 1 h, 2/3 of the reaction mixture was taken for another use, and the remaining material was diluted with EtOAc, washed with water and brine, dried over MgSO 4 , filtered and concentrated. The residue was purified on silica gel, eluting with a 5%-90% EtOAc in hexanes gradient to give the title compound (65 mg, 31%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.78 (s, 3H), 4.11 (d, J=9 Hz, 2H), 4.41 (d, J=9 Hz, 2H), 5.51 (br s, 1H), 6.62 (t, J=5 Hz, 1H), 7.31-7.39 (m, 2H), 8.21-8.30 (m, 2H), 8.36 (d, J=5 Hz, 2H); LC-MS (LC-ES) M+H=330.

Intermediate 106: Racemic 8-(Azetidin-3-ylfluoromethyl)quinoline dihydrochloride

A. Racemic tert-Butyl 3-(hydroxy(quinolin-8-yl)methyl)azetidine-1-carboxylate

To a THF (25 mL) solution of 8-bromoquinoline (1.00 g, 4.81 mmol) at −78° C. was added, dropwise, a 2.5 M solution of n-BuLi in hexanes (1.92 mL, 4.81 mmol). After 30 min, tert-butyl 3-formylazetidine-1-carboxylate (891 mg, 4.81 mmol) in THF (10 ml) was added. After 1 h, the reaction was warmed to 0° C. After another hour, the reaction was quenched with saturated aqueous NH 4 Cl. The mixture was extracted with EtOAc and the combined organics were washed with brine, dried and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel, eluting with a 0% to 30% MeOH in DCM gradient, to afford the title compound (1.25 g, 83%), as a yellowish foam. 1 H NMR (400 MHz, CDCl 3 ) δ 1.42-1.52 (m, 9H), 3.18-3.30 (m, 1H), 3.32-3.44 (m, 1H), 3.66-4.04 (m, 4H), 7.43-7.58 (m, 3H), 7.76-7.83 (m, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.83-8.91 (m, 1H); LC-MS (LC-ES) M+H=315.

B. Racemic tert-Butyl 3-(fluoro(quinolin-8-yl)methyl)azetidine-1-carboxylate

To a DCM (2 mL) solution of tert-butyl 3-(hydroxy(quinolin-8-yl)methyl)azetidine-1-carboxylate (Intermediate 106A) (110 mg, 0.350 mmol) at 0° C. was added, dropwise, DAST (0.35 mL, 0.35 mmol). After 1.5 h, the reaction was warmed to room temperature. After 0.5 h, the mixture was diluted with DCM and saturated aqueous NH 4 Cl. The aqueous layer was separated and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 5%-70% EtOAc-hexanes gradient to give the title compound (47 mg, 43%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 1.45 (s, 9H), 3.29-3.45 (m, 1H), 3.70-3.80 (m, 1H), 4.01 (t, J=8 Hz, 1H), 4.05-4.18 (m, 2H), 6.67-6.89 (m, 1H), 7.44 (d, J=3 Hz, 1H), 7.58 (d, J=7 Hz, 1H), 7.73-7.90 (m, 2H), 8.16 (d, J=8 Hz, 1H), 8.90 (s, 1H); LC-MS (LC-ES) M+H=317.

C. Racemic 8-(Azetidin-3-ylfluoromethyl)quinoline dihydrochioride

To tert-butyl 3-(fluoro(quinolin-8-yl)methyl)azetidine-1-carboxylate (Intermediate 1068) (110 mg, 0.348 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (0.087 mL, 0.35 mmol). The mixture was stirred at room temperature for 1.5 h, and the solvent was removed in vacuo to give the title compound as a tan solid (106 mg, quantitative). LC-MS (LC-ES) M+H=217.

Intermediate 107: (trans)-3-(2,5-Dichlorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(2,5-dichlorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (644 mg, 2.46 mmol) was added to a solution of 2,5-dichlorophenol (300 mg, 2.05 mmol) in tetrahydrofuran (3 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (320 mg, 2.46 mmol) was added, followed by DIAD (0.48 mL, 2.5 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 10%-50% EtOAc-heptane gradient to give the title compound (275 mg, 81%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 2.47-2.58 (m, 2H), 2.76 (ddd, J=14, 7, 4 Hz, 2H), 3.15-3.26 (m, 1H), 3.74 (s, 3H), 4.90 (quin, J=7 Hz, 1H), 6.69 (d, J=2 Hz, 1H), 6.87 (dd, J=9, 2 Hz, 1H), 7.25 (s, 1H); LC-MS (LC-ES) M+H=275, 277, 279 (di-CI pattern).

B. (trans)-3-(2,5-Dichlorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2,5-dichlorophenoxy)cyclobutanecarboxylate (Intermediate 107A) (265 mg, 0.963 mmol) in THF (5 mL), methanol (2.5 mL) and water (2.5 mL) was added LiOH (69 mg, 2.9 mmol). After stirring overnight, the reaction was diluted with water and acidified with 6 N aqueous HCl solution. The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound (175 mg, 70%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.03-2.15 (m, 2H), 2.53-2.66 (m, 3H), 4.81-4.92 (m, 1H), 6.69 (d, J=11 Hz, 1H), 6.80 (td, J=8, 3 Hz, 1H), 7.45 (dd, J=9, 6 Hz, 1H); LC-MS (LC-ES) M−H=259, 261, 263 (di-CI pattern).

Intermediate 108: 3-(2-(Trifluoromethoxy)phenoxy)azetidine hydrochloride

A. tert-Butyl 3-(2-(trifluoromethoxy)phenoxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (355 mg, 1.41 mmol) and 2-(trifluoromethoxy)phenol (250 mg, 1.40 mmol) in DMF (4 mL) was added cesium carbonate (510 mg, 1.57 mmol). The mixture was heated to 80° C. overnight, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 2%-20% EtOAc-hexanes gradient to give the title compound (416 mg, 89%) as a pale yellow oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.40 (s, 9H), 3.78 (d, J=7 Hz, 2H), 4.33 (t, J=8 Hz, 2H), 5.06-5.14 (m, 1H), 6.99 (d, J=8 Hz, 1H), 7.05-7.12 (m, 1H), 7.30-7.46 (m, 2H); LC-MS (LC-ES) M-t-Bu=278.

B. 3-(2-(Trifluoromethoxy)phenoxy)azetidine hydrochloride

To tert-butyl 3-(2-(trifluoromethoxy)phenoxy)azetidine-1-carboxylate (Intermediate 108A) (414 mg, 1.24 mmol) in methanol (2 mL), 4 N HCl in dioxane (8 mL, 32 mmol) was added. After 3 h, the solvent was removed in vacuo and the resulting solid was triturated with diethyl ether to give the title compound as a white solid (297 mg, 89%). 1 H NMR (400 MHz, CD 3 OD) δ 4.01 (dd, J=12, 4 Hz, 2H), 4.46 (dd, J=12, 7 Hz, 2H), 5.17 (t, J=6 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 7.10-7.19 (m, 1H), 7.37 (t, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 9.07 (br s, 2H); LC-MS (LC-ES) M+H=234.

Intermediate 109: (trans)-3-(2-(Trifluoromethoxy)phenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(2-(trifluoromethoxy)phenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 2-(trifluoromethoxy)phenol (0.21 mL, 1.6 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (191 mg, 21%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.29-2.39 (m, 2H), 2.64-2.72 (m, 2H), 3.14-3.22 (m, 1H), 3.65 (s, 3H), 4.88-4.96 (m, 1H), 6.99-7.04 (m, 2H), 7.16-7.26 (m, 1H), 7.29-7.36 (m, 1H); LC-MS (LC-ES) M−H=289.

B. (trans)-3-(2-(Trifluoromethoxy)phenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2-(trifluoromethoxy)phenoxy)cyclobutanecarboxylate (Intermediate 109A) (191 mg, 0.658 mmol) in THF (10 mL) was added LiOH (43 mg, 2.0 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (105 mg, 49%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.29 (ddd, J=13, 10, 6 Hz, 2H), 2.64 (qd, J=7, 4 Hz, 2H), 2.97-3.12 (m, 1H), 4.88 (t, J=6 Hz, 1H), 6.91-7.06 (m, 2H), 7.19-7.40 (m, 2H), 12.32 (br s, 1H); LC-MS (LC-ES) M−H=275.

Intermediate 110: 3-(Benzofuran-7-yloxy)azetidine hydrochloride

A. tert-Butyl 3-(benzofuran-7-yloxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (100 mg, 0.398 mmol) and benzofuran-7-ol (50 mg, 0.373 mmol) in DMF (3 mL) was added cesium carbonate (150 mg, 0.460 mmol). The mixture was heated to 80° C. overnight, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 0%-25% EtOAc-hexanes gradient to give the title compound (60 mg, 56%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.39 (s, 9H), 3.75-3.82 (m, 2H), 4.32-4.38 (m, 2H), 5.14-5.19 (m, 1H), 6.70 (d, J=12 Hz, 1H), 6.94-6.97 (m, 1H), 7.14 (t, J=8 Hz, 1H), 7.27 (d, J=12 Hz, 1H), 7.98-8.00 (m, 1H); LC-MS (LC-ES) M-t-Bu=234.

B. 3-(Benzofuran-7-yloxy)azetidine hydrochloride

To neat tert-butyl 3-(benzofuran-7-yloxy)azetidine-1-carboxylate (Intermediate 110A) (58 mg, 0.20 mmol) was added 4 N HCl in dioxane (2 mL, 8 mmol). After 3 h, the solvent was removed in vacuo and the resulting solid was triturated with diethyl ether to give the title compound as a white solid (40 mg, 88%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 4.04-4.11 (m, 2H), 4.44-4.51 (m, 2H), 5.20-5.27 (m, 1H), 6.72 (d, J=12 Hz, 1H), 6.96-6.98 (m, 1H), 7.14 (t, J=8 Hz, 1H), 7.29 (d, J=12 Hz, 1H), 7.98-8.01 (m, 1H), 9.19 (br s, 2H); LC-MS (LC-ES) M+H=190.

Intermediate 111: (trans)-3-(Benzofuran-7-yloxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(benzofuran-7-yloxy)cyclobutanecarboxylate

Triphenylphosphine (892 mg, 3.40 mmol) was added to a solution of benzofuran-7-ol (380 mg, 2.83 mmol) in tetrahydrofuran (7 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.36 mL, 3.4 mmol) was added, followed by DIAD (0.66 mL, 3.4 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (373 mg, 45%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.34-2.46 (m, 2H), 2.65-2.73 (m, 2H), 3.15-3.25 (m, 1H), 3.63 (s, 3H), 4.90-5.01 (m, 1H), 6.69 (d, J=8 Hz, 1H), 6.87-6.91 (m, 1H), 7.10 (t, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.90-7.93 (m, 1H); LC-MS (LC-ES) M+H=247.

B. (trans)-3-(Benzofuran-7-yloxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(benzofuran-7-yloxy)cyclobutanecarboxylate (Intermediate 111A) (373 mg, 1.52 mmol) in THF (10 mL) was added LiOH (109 mg, 4.54 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (332 mg, 86%). LC-MS (LC-ES) M+H=233.

Intermediate 112: (trans)-3-((3-Bromobenzofuran-7-yl)oxy)cyclobutanecarboxylic acid

A. 3-Bromo-7-methoxybenzofuran

Bromine (0.33 mL, 6.4 mmol) was added dropwise to a solution of 7-methoxybenzofuran (0.70 mL, 5.4 mmol) in carbon disulfide (25 mL) cooled to 0° C. After 1 h, the reaction mixture was concentrated, and ethanol (25 mL) and sodium ethoxide (548 mg, 8.05 mmol) were added. After stirring overnight, the reaction was concentrated. The crude material was purified on silica gel, eluting with 0%-40% EtOAc in hexanes, and then reverse phase silica gel, eluting with 10%-100% MeCN in water (with 0.1% TFA) to afford the title compound (1.25 g, 83%) as a yellowish foam. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.91 (s, 3H), 6.82-6.91 (m, 2H), 7.36 (d, J=9 Hz, 1H), 8.08 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=226, 228 (Br pattern).

B. 3-Bromobenzofuran-7-ol

A 1 M solution of boron trichloride in DCM (8.92 mL, 8.92 mmol) was added to 3-bromo-7-methoxybenzofuran (Intermediate 112A) (0.60 mL, 3.0 mmol) and TBAI (1.32 g, 3.57 mmol) in DCM (6 mL) cooled to −78° C. After 6 h, the reaction was then quenched with iced water (50 mL). After stirring overnight, the aqueous layer was basified with 5 N aqueous NaOH (to pH=10), stirred for 1 h, neutralized with 1 N aqueous HCl (to pH=7), and extracted with DCM (3×). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified over silica gel, eluting with 0%-100% EtOAc: EtOH (3:1) in hexanes to give the title compound (660 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 6.70 (d, J=8 Hz, 1H), 6.81 (d, J=2 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 8.04 (d, J=2 Hz, 1H), 10.33 (s, 1H); LC-MS (LC-ES) M+H=213, 215 (Br pattern).

C. (trans)-Methyl 3-((3-bromobenzofuran-7-yl)oxy)cyclobutanecarboxylate

Triphenylphosphine (443 mg, 1.69 mmol) was added to a solution of 3-bromobenzofuran-7-ol (Intermediate 112B) (300 mg, 1.41 mmol) in tetrahydrofuran (2 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.18 mL, 1.7 mmol) was added, followed by DIAD (0.33 mL, 1.7 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-70% EtOAc-hexanes gradient to give the title compound (343 mg, 63%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.30-2.44 (m, 2H), 2.69 (ddd, J=14, 7.4 Hz, 2H), 3.12-3.21 (m, 1H), 3.31 (s, 3H), 4.99 (t, J=7 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 6.87 (d, J=2 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 8.08 (d, J=2 Hz, 1H); LC-MS (LC-ES) M+H=325, 327 (Br pattern).

D. (trans)-3-((3-Bromobenzofuran-7-yl)oxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(benzofuran-7-yloxy)cyclobutanecarboxylate (Intermediate 112C) (343 mg, 1.06 mmol) in THF (5 mL) was added LiOH (76 mg, 3.2 mmol) in water (2.5 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound (315 mg, 88%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.32-2.44 (m, 2H), 2.66 (d, J=6 Hz, 2H), 3.05-3.14 (m, 1H), 4.97 (t, J=6 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 6.87 (s, 1H), 7.32 (d, J=8 Hz, 1H), 8.08 (s, 1H), 12.34 (br s, 1H); LC-MS (LC-ES) M+H=311, 313 (Br pattern).

Intermediate 113: (trans)-3-(5-Chloro-2-(difluoromethoxy)phenoxy)cyclobutanecarboxylic acid

A. 2-(Benzyloxy)-4-chlorobenzaldehyde

To a stirred solution of 4-chloro-2-hydroxybenzaldehyde (5.00 g, 12.8 mmol) in DMF (20 mL) was added potassium carbonate (2.12 g, 15.3 mmol) and benzyl bromide (1.72 mL, 15.3 mmol). After 3 h, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The organic layers were dried over Na 2 SO 4 , evaporated and dried under vacuum. The residue was purified on silica gel eluting with a 0%-40% EtOAc in hexanes gradient to give the title compound (3.17 g, 98%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.33 (s, 2H) 7.04-7.23 (m, 1H) 7.25-7.58 (m, 6H) 7.72 (d, J=8 Hz, 1H) 10.34 (s, 1H); LC-MS (LC-ES) M+H=247, 249 (CI pattern).

B. 2-(Benzyloxy)-4-chlorophenol

3-Chlorobenzoperoxoic acid (5.54 g, 3.21 mmol) was added to a solution of 2-(benzyloxy)-4-chlorobenzaldehyde (Intermediate 113A) (3.17 g, 12.9 mmol) in DCM (50 mL) and stirred at 40° C. overnight, cooled and washed with NaHCO 3 (saturated, 3×) and brine. The organic layer was dried over Na 2 SO 4 and evaporated. The residue was dissolved in THF (50 mL) and water (25 mL), and lithium hydroxide (923 mg, 38.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Citric acid was added until pH neutral, and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified on silica gel eluting with a 0%-40% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (2.08 g, 63%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.12 (s, 2H), 6.80 (d, J=1 Hz, 2H), 7.03 (s, 1H), 7.23-7.53 (m, 5H), 9.31 (s, 1H); LC-MS (LC-ES) M−H=233.

C. 2-(Benzyloxy)-4-chloro-1-(difluoromethoxy)benzene

To a stirred, cooled (−78° C.) solution of 2-(benzyloxy)-4-chlorophenol (Intermediate 1138) (2.08 g, 8.86 mmol) and potassium hydroxide (9.95 g, 177 mmol) in acetonitrile (80 mL) and water (80 mL) was added diethyl (bromodifluoromethyl)phosphonate (3.15 mL, 17.7 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was extracted twice with Et 2 O. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with a 0%-50% EtOAc in hexanes gradient to give the title compound (1.94 g, 77%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.20 (s, 2H), 6.91-7.15 (m, 2H), 7.15-7.32 (m, 1H), 7.32-7.51 (m, 6H); LC-MS (LC-ES) M−H=283, 285 (CI pattern).

D. 5-Chloro-2-(difluoromethoxy)phenol

To a stirred solution of 2-(benzyloxy)-1-(difluoromethoxy)-4-fluorobenzene (Intermediate 113C) (332 mg, 1.17 mmol) in methanol (5 mL) under a nitrogen atmosphere was added Pd/C (60 mg, 0.56 mmol). The reaction vessel was fitted with a hydrogen filled balloon and stirred overnight under a hydrogen atmosphere. The mixture was filtered through a pad of Celite®, washing with DCM and EtOH. The filtrate was evaporated to dryness to give the crude title compound (194 mg, 86%), which was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 6.79-7.19 (m, 4H) 10.42 (s, 1H); LC-MS (LC-ES) M−H=193, 195 (CI pattern).

E. (trans)-Methyl 3-(5-chloro-2-(difluoromethoxy)phenoxy)cyclobutanecarboxylate

Triphenylphosphine (314 mg, 1.20 mmol) was added to a solution of 5-chloro-2-(difluoromethoxy)phenol (Intermediate 113D) (194 mg, 0.997 mmol) in tetrahydrofuran (1 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.13 mL, 1.2 mmol) was added, followed by DIAD (0.23 mL, 1.2 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-70% EtOAc-hexanes gradient to give the title compound (192 mg, 63%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.32-2.42 (m, 2H), 2.64-2.72 (m, 2H), 3.20 (dd, J=5, 5 Hz, 1H), 3.32 (s, 3H), 4.93 (dd, J=7, 6 Hz, 1H), 6.90-7.09 (m, 3H), 7.21 (d, J=9 Hz, 1H); LC-MS (LC-ES) peak at T=0.91 min.

F. (trans)-3-(5-Chloro-2-(difluoromethoxy)phenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(5-chloro-2-(difluoromethoxy)phenoxy)cyclobutanecarboxylate (Intermediate 113E) (192 mg, 0.626 mmol) in THF (5 mL) was added LiOH (45 mg, 1.9 mmol) in water (2.5 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound (200 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.32-2.44 (m, 2H), 2.66 (d, J=6 Hz, 2H), 3.05-3.14 (m, 1H), 4.97 (t, J=6 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 6.87 (s, 1H), 7.32 (d, J=8 Hz, 1H), 8.08 (s, 1H), 12.34 (br s, 1H); LC-MS (LC-ES) M−H=291, 293 (CI pattern).

Intermediate 114: (trans)-3-(5-Chloro-2-methoxyphenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(5-chloro-2-methoxyphenoxy)cyclobutanecarboxylate

Triphenylphosphine (500 mg, 1.90 mmol) was added to a solution of 5-chloro-2-methoxyphenol (250 mg, 1.58 mmol) in tetrahydrofuran (1 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.30 mL, 1.9 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 12 h and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient to give the title compound (228 mg, 30%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.25-2.38 (m, 2H), 2.63 (ddd, J=13, 7, 4 Hz, 2H), 3.15 (dt, J=10, 5 Hz, 1H), 3.63 (s, 3H), 3.72 (s, 3H), 4.72-4.82 (m, 1H), 6.72 (d, J=2 Hz, 1H), 6.87-6.98 (m, 2H); LC-MS (LC-ES) M+H-OMe=239, 241 (CI pattern).

B. (trans)-3-(5-Chloro-2-methoxyphenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(5-chloro-2-methoxyphenoxy)cyclobutanecarboxylate (Intermediate 114A) (306 mg, 1.13 mmol) in THF (10 mL) was added LiOH (81 mg, 3.4 mmol) in water (5 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (300 mg, 100%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.13-2.30 (m, 2H), 2.54-2.65 (m, 2H), 2.92-3.08 (m, 1H), 3.72 (s, 3H), 4.72-4.85 (m, 1H), 6.71 (s, 1H), 6.85-6.95 (m, 2H), 12.30 (br s, 1H); LC-MS (LC-ES) M−H=255, 257 (CI pattern).

Intermediate 115: (trans)-3-(4-Fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(4-fluoro-2-methoxyphenoxy)cyclobutanecarboxylate

Triphenylphosphine (830 mg, 3.16 mmol) was added to a solution of 4-fluoro-2-methoxyphenol (0.300 mL, 2.63 mmol) in tetrahydrofuran (2 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.34 mL, 3.2 mmol) was added, followed by DIAD (0.61 mL, 3.2 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 12 h and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient to give the title compound (666 mg, 100%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.24-2.40 (m, 2H), 2.58 (ddd, J=13, 7, 4 Hz, 2H), 3.09-3.18 (m, 1H), 3.62 (s, 3H), 3.72 (s, 3H), 4.71 (t, J=7 Hz, 1H), 6.56-6.66 (m, 1H), 6.67-6.77 (m, 1H), 6.88 (d, J=3 Hz, 1H); LC-MS (LC-ES) M+H=255.

B. (trans)-3-(4-Fluoro-2-methoxyphenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(4-fluoro-2-methoxyphenoxy)cyclobutanecarboxylate (Intermediate 115A) (666 mg, 2.62 mmol) in THF (15 mL) was added LiOH (190 mg, 7.86 mmol) in water (7.5 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (690 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.21-2.38 (m, 2H), 2.53-2.65 (m, 2H), 2.95-3.08 (m, 1H), 3.74 (s, 3H), 4.69 (t, J=7 Hz, 1H), 6.61 (td, J=9, 3 Hz, 1H), 6.66-6.72 (m, 1H), 6.89 (d, J=3 Hz, 1H), 12.27 (br s, 1H); LC-MS (LC-ES) M−H=239.

Intermediate 116: (trans)-3-(2-(Difluoromethoxy)phenoxy)cyclobutanecarboxylic acid

A. 2-(Benzyloxy)phenol

To a stirred solution of pyrocatechol (3.00 g, 27.2 mmol) in DMF (30 mL) was added potassium carbonate (4.14 g, 30.0 mmol) and benzyl bromide (3.89 mL, 32.7 mmol). After 3 h, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified on silica gel, eluting with a 0%-30% EtOAc in hexanes gradient to give the title compound (3.56 g, 59%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.07 (s, 2H), 6.64-6.88 (m, 3H), 6.94 (dd, J=8, 1 Hz, 1H), 7.19-7.41 (m, 3H), 7.45 (d, J=7 Hz, 2H), 8.97 (s, 1H); LC-MS (LC-ES) M+H=201.

B. 1-(Benzyloxy)-2-(difluoromethoxy)benzene

To a stirred, cooled (−78° C.) solution of 2-(benzyloxy)phenol (Intermediate 116A) (2.50 g, 12.5 mmol) and potassium hydroxide (14.0 g, 250 mmol) in acetonitrile (120 mL) and water (120 mL) was added diethyl (bromodifluoromethyl)phosphonate (4.44 mL, 25.0 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was extracted twice with Et 2 O. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 0%-50% EtOAc in hexanes gradient to give the title compound (1.54 g, 49%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 5.15 (s, 2H), 6.87-7.00 (m, 2H), 7.07 (t, J=76 Hz, 1H), 7.12-7.49 (m, 7H); LC-MS (LC-ES) M−H=249.

C. 2-(Difluoromethoxy)phenol

To a stirred solution of 1-(benzyloxy)-2-(difluoromethoxy)benzene (Intermediate 116B) (1.53 g, 6.11 mmol) in ethanol (15 mL) under a nitrogen atmosphere was added Pd/C (200 mg, 1.88 mmol). The reaction vessel was degassed, fitted with a hydrogen filled balloon and stirred 14 h under a hydrogen atmosphere. The mixture was filtered through a pad of Celite®, washing with DCM. The filtrate was concentrated to give the crude title compound (194 mg, 86%), which was used without further purification. LC-MS (LC-ES) M−H=159.

D. (trans)-Methyl 3-(2-(difluoromethoxy)phenoxy)cyclobutanecarboxylate

Triphenylphosphine (786 mg, 3.00 mmol) was added to a solution of 2-(difluoromethoxy)phenol (Intermediate 116C) (400 mg, 2.50 mmol) in tetrahydrofuran (2 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.32 mL, 3.0 mmol) was added, followed by DIAD (0.58 mL, 3.0 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days, and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-50% EtOAc-hexanes gradient to give the title compound (228 mg, 30%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.32-2.41 (m, 2H), 2.64-2.70 (m, 2H), 3.15-3.20 (m, 1H), 3.32 (s, 3H), 4.84-4.90 (m, 1H), 6.92-6.99 (m, 2H), 7.07 (t, J=76 Hz, 1H), 7.14-7.21 (m, 2H); LC-MS (LC-ES) peak at T=0.85 min.

E. (trans)-3-(2-(Difluoromethoxy)phenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2-(difluoromethoxy)phenoxy)cyclobutanecarboxylate (Intermediate 116D) (228 mg, 0.837 mmol) in THF (5 mL) was added LiOH (60 mg, 2.5 mmol) in water (2.5 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound (221 mg, 100%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.25-2.32 (m, 2H), 2.56-2.65 (m, 2H), 3.01-3.09 (m, 1H), 4.84 (t, J=7 Hz, 1H), 6.86-6.95 (m, 2H), 7.05 (t, J=76 Hz, 1H), 7.11-7.19 (m, 2H), 12.31 (br s, 1H); LC-MS (LC-ES) M−H=257.

Intermediate 117: (trans)-3-((3-Fluoroquinolin-8-yl)oxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-((3-fluoroquinolin-8-yl)oxy)cyclobutanecarboxylate

Triphenylphosphine (386 mg, 1.47 mmol) was added to a solution of 3-fluoroquinolin-8-ol (200 mg, 1.23 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (0.16 mL, 1.5 mmol) was added, followed by DIAD (0.29 mL, 1.5 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (438 mg, 65%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.38-2.52 (m, 2H), 2.68-2.71 (m, 2H), 3.15-3.22 (m, 1H), 3.30 (s, 3H), 4.94-5.01 (m, 1H), 6.92-6.97 (m, 1H), 7.45-7.55 (m, 2H), 8.13-8.21 (m, 1H), 8.85 (s, 1H); LC-MS (LC-ES) M+H=276.

B. (trans)-3-((3-Fluoroquinolin-8-yl)oxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(4-fluoro-2-methoxyphenoxy)cyclobutanecarboxylate (Intermediate 117A) (440 mg, 1.60 mmol) in THF (20 mL) was added LiOH (115 mg, 4.80 mmol) in water (10 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (430 mg, 100%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.42-2.48 (m, 2H), 2.70-2.77 (m, 2H), 3.09-3.14 (m, 1H), 4.96-5.04 (m, 1H), 6.92-6.95 (m, 1H), 7.47-7.55 (m, 2H), 8.16-8.20 (m, 1H), 8.86 (s, 1H), 12.35 (br s, 1H); LC-MS (LC-ES) M+H=262.

Intermediate 118: (trans)-3-(2-Chlorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(2-chlorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 2-chlorophenol (0.17 mL, 1.6 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (365 mg, 83%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.38 (ddd, J=13, 10, 6 Hz, 2H), 2.68 (ddd, J=13, 7, 4 Hz, 2H), 3.11-3.20 (m, 1H), 3.60 (s, 3H), 4.88 (t, J=7 Hz, 1H), 6.77-7.00 (m, 2H), 7.24 (td, J=8, 2 Hz, 1H), 7.40 (dd, J=8, 2 Hz, 1H); LC-MS (LC-ES) M+H=241, 243 (CI pattern).

B. (trans)-3-(2-Chlorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2-chlorophenoxy)cyclobutanecarboxylate (Intermediate 118A) (365 mg, 1.52 mmol) in THF (10 mL) was added LiOH (109 mg, 4.55 mmol) in water (5 mL). After 1 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (327 mg, 93%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.28-2.35 (m, 2H), 2.65 (ddd, J=13, 7, 4 Hz, 2H), 3.01-3.10 (m, 1H), 4.86 (t, J=7 Hz, 1H), 6.85-6.92 (m, 2H), 7.24 (td, J=8, 2 Hz, 1H), 7.40 (dd, J=8, 2 Hz, 1H), 12.32 (s, 1H); LC-MS (LC-ES) M−H=225, 227 (CI pattern).

Intermediate 119: (trans)-3-(3,5-Difluorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(3,5-difluorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 3,5-difluorophenol (208 mg, 1.60 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (371 mg, 82%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.22-2.39 (m, 2H), 2.63-2.72 (m, 2H), 3.17 (dd, J=5, 5 Hz, 1H), 3.61 (s, 3H), 4.83 (dd, J=7, 6 Hz, 1H), 6.56 (dd, J=9, 2 Hz, 2H), 6.72-6.89 (m, 1H); LC-MS (LC-ES) M−H=240.

B. (trans)-3-(3,5-Difluorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(3,5-difluorophenoxy)cyclobutanecarboxylate (Intermediate 119A) (371 mg, 1.53 mmol) in THF (10 mL) was added LiOH (110 mg, 4.60 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (325 mg, 91%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.19-2.31 (m, 2H), 2.58-2.63 (m, 2H), 3.00-3.09 (m, 1H), 4.82 (dd, J=7, 6 Hz, 1H), 6.49-6.60 (m, 2H), 6.75 (tt, J=9, 2 Hz, 1H), 12.31 (br s, 1H); LC-MS (LC-ES) M−H=227.

Intermediate 120: (trans)-3-(2-Methoxyphenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(2-methoxyphenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 2-methoxyphenol (0.18 mL, 1.6 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (206 mg, 54%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.30-2.40 (m, 2H), 2.58-2.67 (m, 2H), 3.10-3.20 (m, 1H), 3.63 (s, 3H), 3.73 (s, 3H), 4.71-4.79 (m, 1H), 6.68-6.81 (m, 1H), 6.78-6.89 (m, 2H), 6.91-6.95 (m, 1H); LC-MS (LC-ES) M+H-OMe=205.

B. (trans)-3-(2-Methoxyphenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(2-methoxyphenoxy)cyclobutanecarboxylate (Intermediate 120A) (206 mg, 0.872 mmol) in THF (10 mL) was added LiOH (63 mg, 2.6 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (209 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.24-2.31 (m, 2H), 2.54-2.62 (m, 2H), 2.98-3.08 (m, 1H), 3.71 (s, 3H), 4.74 (t, J=7 Hz, 1H), 6.71 (dd, J=8, 2 Hz, 1H), 6.76-6.88 (m, 2H), 6.91-6.96 (m, 1H), 12.30 (br s, 1H); LC-MS (LC-ES) M−H=221.

Intermediate 121: (trans)-3-(3-Ethylphenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(3-ethylphenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 3-ethylphenol (0.20 mL, 1.6 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (169 mg, 41%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.13 (t, J=8 Hz, 3H), 2.22-2.31 (m, 2H), 2.45-2.56 (m, 2H), 2.58-2.65 (m, 2H), 3.10-3.19 (m, 1H), 3.62 (s, 3H), 4.72-4.81 (m, 1H), 6.56-6.61 (m, 2H), 6.75 (d, J=8 Hz, 1H), 7.11-7.16 (m, 1H); LC-MS (LC-ES) M+H=235.

B. (trans)-3-(3-Ethylphenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(3-ethylphenoxy)cyclobutanecarboxylate (Intermediate 121A) (169 mg, 0.721 mmol) in THF (10 mL) was added LiOH (52 mg, 2.2 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (172 mg, 96%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.13 (t, J=8 Hz, 3H), 2.15-2.29 (m, 2H), 2.42-2.65 (m, 4H), 2.92-3.02 (m, 1H), 4.68-4.79 (m, 1H), 6.56-6.62 (m, 2H), 6.75 (d, J=8 Hz, 1H), 7.11-7.16 (m, 1H), 12.34 (br s, 1H); LC-MS (LC-ES) M−H=219.

Intermediate 122: (trans)-3-(3-Chlorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(3-chlorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 3-chlorophenol (206 mg, 1.60 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (291 mg, 72%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.28-2.36 (m, 2H), 2.61-2.68 (m, 2H), 3.11-3.20 (m, 1H), 3.65 (s, 3H), 4.80-4.88 (m, 1H), 6.76-6.78 (m, 1H), 6.83-6.86 (m, 1H), 6.95-6.98 (m, 1H), 7.24-7.29 (m, 1H); LC-MS (LC-ES) M+H=241, 243 (CI pattern).

B. (trans)-3-(3-Chlorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(3-chlorophenoxy)cyclobutanecarboxylate (Intermediate 122A) (291 mg, 1.21 mmol) in THF (10 mL) was added LiOH (87 mg, 3.6 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (282 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.24-2.32 (m, 2H), 2.58-2.65 (m, 2H), 3.01-3.10 (m, 1H), 4.78-4.86 (m, 1H), 6.76-6.79 (m, 1H), 6.83-6.86 (m, 1H), 6.94-6.98 (m, 1H), 7.24-7.30 (m, 1H), 12.44 (br s, 1H); LC-MS (LC-ES) M−H=225, 227 (CI pattern).

Intermediate 123: (trans)-3-(3-Fluorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(3-fluorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 3-fluorophenol (0.14 mL, 1.6 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (291 mg, 72%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.22-2.35 (m, 2H), 2.60-2.68 (m, 2H), 3.12-3.21 (m, 1H), 3.62 (s, 3H), 4.74-4.82 (m, 1H), 6.59-6.65 (m, 2H), 6.70-6.76 (m, 1H), 7.21-7.31 (m, 1H); LC-MS (LC-ES) M+H+CH 3 CN=266.

B. (trans)-3-(3-Fluorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(3-fluorophenoxy)cyclobutanecarboxylate (Intermediate 123A) (330 mg, 1.47 mmol) in THF (10 mL) was added LiOH (106 mg, 4.42 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (325 mg, quantitative). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.21-2.31 (m, 2H), 2.57-2.67 (m, 2H), 3.05 (dt, J=10, 5 Hz, 1H), 4.70-4.81 (m, 1H), 6.59-6.65 (m, 2H), 6.94-6.98 (m, 1H), 7.21-7.31 (m, 1H), 12.32 (br s, 1H); LC-MS (LC-ES) M−H=209.

Intermediate 124: (trans)-3-(3-Chloro-5-fluorophenoxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(3-Chloro-5-fluorophenoxy)cyclobutanecarboxylate

Triphenylphosphine (504 mg, 1.92 mmol) was added to a solution of 3-chloro-5-fluorophenol (0.17 mL, 1.6 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (250 mg, 1.92 mmol) was added, followed by DIAD (0.37 mL, 1.9 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give the title compound (291 mg, 72%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.25-2.31 (m, 2H), 2.60-2.70 (m, 2H), 3.12-3.21 (m, 1H), 3.62 (s, 3H), 4.80-4.89 (m, 1H), 6.51-6.58 (m, 1H), 6.70-6.78 (m, 1H), 6.95-6.98 (m, 1H); LC-MS (LC-ES) M-CO 2 Me=201, 203 (CI pattern).

B. (trans)-3-(3-Chloro-5-fluorophenoxy)cyclobutanecarboxylic acid

To a solution of (trans)-Methyl 3-(3-Chloro-5-fluorophenoxy)cyclobutanecarboxylate (Intermediate 124A) (295 mg, 1.14 mmol) in THF (10 mL) was added LiOH (82 mg, 3.4 mmol) in water (5 mL). After 3 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (244 mg, 65%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.19-2.30 (m, 2H), 2.58-2.67 (m, 2H), 3.01-3.11 (m, 1H), 4.84 (dd, J=7, 6 Hz, 1H), 6.68-6.75 (m, 2H), 6.94-6.98 (m, 1H), 12.30 (br s, 1H); LC-MS (LC-ES) M+H=245, 247 (CI pattern).

Intermediate 125: (trans)-3-((5-Fluoroquinolin-8-yl)oxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-((5-fluoroquinolin-8-yl)oxy)cyclobutanecarboxylate

Triphenylphosphine (1.21 g, 4.60 mmol) was added to a solution of 5-fluoroquinolin-8-ol (500 mg, 3.06 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0° C., and methyl 3-hydroxycyclobutanecarboxylate (0.49 mL, 4.6 mmol) was added, followed by DIAD (0.89 mL, 4.6 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give a mixture of cis and trans isomers which were separated on a Whelk 0 RR 20×250 mm column eluting with 40% EtOH in hexanes to give the title compound (415 mg, 49%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.48-2.55 (m, 2H), 2.77 (ddd, J=13, 7, 4 Hz, 2H), 3.21-3.29 (m, 1H), 3.66 (s, 3H), 5.04 (t, J=7 Hz, 1H), 6.96 (dd, J=9, 5 Hz, 1H), 7.32 (dd, J=10, 9 Hz, 1H), 7.68 (dd, J=8, 4 Hz, 1H), 8.44 (dd, J=8, 2 Hz, 1H), 8.97 (dd, J=4, 2 Hz, 1H); LC-MS (LC-ES) M+H=276.

B. (trans)-3-((5-Fluoroquinolin-8-yl)oxy)cyclobutanecarboxylic acid

To a solution of (trans)-Methyl 3-((5-fluoroquinolin-8-yl)oxy)cyclobutanecarboxylate (Intermediate 125A) (415 mg, 1.51 mmol) in THF (10 mL) was added LiOH (108 mg, 4.52 mmol) in water (2 mL). After 2 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (400 mg, 100%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.38-2.50 (m, 2H), 2.66-2.75 (m, 2H), 3.05-3.12 (m, 1H), 4.92-5.01 (m, 1H), 6.89-6.93 (m, 1H), 7.23-7.31 (m, 1H), 7.61-7.66 (m, 1H), 8.38-8.42 (m, 1H), 8.91-8.95 (m, 1H), 12.38 (br s, 1H); LC-MS (LC-ES) M+H=262.

Intermediate 126: (trans)-3-((6-Fluoroquinolin-8-yl)oxy)cyclobutanecarboxylic acid

A. 6-Fluoroquinolin-8-ol

Aluminium chloride (4.52 g, 33.9 mmol) was added to a solution of 6-fluoro-8-methoxyquinoline (2.00 g, 11.3 mmol) in 1,2-dichloroethane (20 mL), and the reaction mixture was heated to 50° C. After 3 h, the mixture was cooled to 0° C., quenched with saturated aqueous NaHCO 3 until pH neutral and filtered. The collected solid was retained. The aqueous layer of the filtrate was extracted with DCM (3×), and the combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel using 0%-100% EtOAc: EtOH (3:1) in hexanes to afford 186 mg of the title compound. The previously retained solid was stirred in THF (20 mL) overnight, and the mixture was filtered through Celite. The filtrate was concentrated and dried under vacuum to afford an additional 500 mg the title compound (37% total yield). LC-MS (LC-ES) peak at T=0.37 min; M+H=164.

B. (trans)-Methyl 3-((6-fluoroquinolin-8-yl)oxy)cyclobutanecarboxylate

Triphenylphosphine (916 mg, 3.49 mmol) was added to a solution of 6-fluoroquinolin-8-ol (Intermediate 126A) (380 mg, 2.23 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0° C., and methyl 3-hydroxycyclobutanecarboxylate (0.37 mL, 3.5 mmol) was added, followed by DIAD (0.68 mL, 3.5 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc-hexanes gradient to give a mixture of cis and trans isomers which were separated on an IC 30×250 mm column eluting with 50% EtOH in hexanes to give the title compound (137 mg, 21%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.48-2.59 (m, 2H), 2.82 (ddd, J=14, 7, 5 Hz, 2H), 3.22-3.32 (m, 1H), 3.31 (s, 3H), 5.07 (t, J=7 Hz, 1H), 6.91 (dd, J=11, 3 Hz, 1H), 7.31 (dd, J=9, 3 Hz, 1H), 7.59 (dd, J=8, 4 Hz, 1H), 8.30 (dd, J=8, 2 Hz, 1H), 8.83 (dd, J=4, 2 Hz, 1H); LC-MS (LC-ES) M+H=276.

C. (trans)-3-((6-Fluoroquinolin-8-yl)oxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-((6-fluoroquinolin-8-yl)oxy)cyclobutanecarboxylate (Intermediate 1268) (167 mg, 0.607 mmol) in THF (5 mL) was added LiOH (44 mg, 1.8 mmol) in water (1 mL). After 2 h, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (155 mg, 94%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.41-2.51 (m, 2H), 2.71-2.79 (m, 2H), 3.07-3.15 (m, 1H), 4.98-5.05 (m, 1H), 6.84-6.89 (m, 1H), 7.25-7.30 (m, 1H), 7.53-7.58 (m, 1H), 8.25-8.30 (m, 1H), 8.78-8.82 (m, 1H), 12.35 (br s, 1H); LC-MS (LC-ES) M+H=262.

Intermediate 127: 2-(3-Aminocyclobutyl)propan-2-ol

A. 3-(2-Hydroxypropan-2-yl)cyclobutanol

To a diethyl ether solution (30 mL) containing methyl magnesium bromide (7.63 mL of a 3.0 M diethyl ether solution) was added a diethyl ether solution (5 mL) containing ethyl 3-hydroxycyclobutane carboxylate (2.05 g, 6.94 mmol), dropwise. After 2 h the reaction was carefully quenched with 3 M aqueous HCl. MgSO 4 was added until the evolution of gas stopped. The solution was filtered, and the solvent removed in vacuo yielding a viscous oil which was purified by silica gel chromatography (50%-100% EtOAc in hexanes) to give the title compound (419 mg, 46%). 1 H NMR (CDCl 3 ) δ 1.13 (s, 6H), 1.74-1.86 (m, 4H), 2.23-2.39 (m, 2H), 2.66 (br s, 1H), 4.03-4.09 (m, 1H).

B. 3-(2-Hydroxypropan-2-yl)cyclobutyl4-methylbenzenesulfonate

To a pyridine solution (15 mL) containing 3-(2-hydroxypropan-2-yl)cyclobutanol (Intermediate 127A) (415 mg, 3.19 mmol) cooled to 0° C. was added p-toluenesulfonyl chloride (638 mg, 3.35 mmol). The reaction was slowly allowed to warm to room temperature overnight, and the organics were taken up in Et 2 O. The solution was washed with water, saturated NaHCO 3 and saturated NaHSO 4 followed by drying over MgSO 4 . The solvent was removed in vacuo yielding the title compound (792 mg) as a viscous oil which was taken on crude. 1 H NMR (CDCl 3 ) δ 1.08 (s, 6H), 1.71-1.88 (m, 1H), 1.98-2.11 (m, 2H), 2.12-2.23 (m, 2H), 2.45 (s, 3H), 4.65 (quin, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H).

C. 2-(3-Azidocyclobutyl)propan-2-ol

A DMF solution (40 mL) of 3-(2-hydroxypropan-2-yl)cyclobutyl 4-methylbenzenesulfonate (Intermediate 127B) (2.50 g, 8.79 mmol) and sodium azide (686 mg, 10.6 mmol) was heated to 90° C. overnight. Upon cooling, the organics were taken up in Et 2 O and washed with water (2×) and saturated NaHCO 3 followed by drying over MgSO 4 . The solvent was carefully removed in vacuo yielding the title compound (1.19 g) as an oil which was taken on crude. 1 H NMR (CDCl 3 ) δ 1.14 (s, 6H), 2.03-2.16 (m, 2H), 2.26-2.34 (m, 2H), 2.35-2.44 (m, 1H), 3.87-4.01 (m, 1H).

D. 2-(3-Aminocyclobutyl)propan-2-ol

To an EtOH solution (25 mL) containing 10% Pd/C (809 mg, wet Degussa) was added an EtOH solution (5 mL) of 2-(3-azidocyclobutyl)propan-2-ol (Intermediate 127C) (1.18 g, 7.60 mmol). The flask was then evacuated under vacuum and refilled with hydrogen via a balloon. This process was repeated twice more and then the reaction was stirred under 1 atmosphere of hydrogen overnight. The catalyst was removed under vacuum filtration though a plug of Celite®. The Celite® was rinsed with DCM and the solvent removed in vacuo yielding the title compound (920 mg) as an oil. 1 H NMR (CDCl 3 ) δ 1.12 (s, 6H), 1.66-1.77 (m, 2H), 2.16-2.28 (m, 2H), 2.27-2.42 (m, 1H), 3.40-3.52 (m, 1H).

Intermediate 128: (trans)-3-(Quinazolin-8-yloxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(quinazolin-8-yloxy)cyclobutanecarboxylate

Triphenylphosphine (538 mg, 2.05 mmol) was added to a solution of quinazolin-8-ol (250 mg, 1.71 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (245 mg, 1.88 mmol) was added, followed by DIAD (0.40 mL, 2.1 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 2 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc: EtOH (3:1) in hexanes gradient to give the title compound (178 mg, 40%) as a light brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ 2.65-2.75 (m, 2H), 2.80-2.90 (m, 2H), 3.20-3.28 (m, 1H), 3.74 (s, 3H), 5.10-5.15 (m, 1H), 7.04-7.08 (m, 1H), 7.47-7.57 (m, 2H), 9.35-9.37 (m, 2H); LC-MS (LC-ES) M−H=258.

B. (trans)-3-(Quinazolin-8-yloxylcyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(quinazolin-8-yloxy)cyclobutanecarboxylate (Intermediate 128A) (175 mg, 0.678 mmol) in THF (3 mL) was added LiOH hydrate (85 mg, 2.0 mmol) in water (1.5 mL). After stirring overnight, the reaction was adjusted to pH=4.5 with the addition of 10% aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (190 mg, quantitative) as a tan solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.40-2.49 (m, 2H), 2.68-2.77 (m, 2H), 3.08-3.17 (m, 1H), 4.99-5.05 (m, 1H), 7.21-7.25 (m, 1H), 7.58-7.66 (m, 2H), 9.24-9.27 (m, 1H), 9.54 (s, 1H), 12.40 (br s, 1H).

Intermediate 129: (trans)-3-Hydroxy-N-(thiazol-2-yl)cyclobutanecarboxamide

A. (trans)-Methyl 3-((tert-butyldiphenylsilyl)oxy)cyclobutanecarboxylate

To (trans)-methyl 3-hydroxycyclobutanecarboxylate (1.00 g, 7.68 mmol) and imidazole (1.15 g, 16.9 mmol) in DMF (35 mL) at 0° C. was added tert-butylchlorodiphenylsilane (2.32 g, 8.45 mmol). The reaction was warmed to room temperature overnight, and was concentrated, diluted with EtOAc, and washed with water and brine. The organic layer was separated, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel chromatography (0%-30% EtOAc in hexanes) to give the title compound (3.05 g, quantitative) as a clear oil. 1 H NMR (CDCl 3 ) δ 1.01 (s, 9H), 2.28-2.44 (m, 4H), 2.92-2.98 (m, 1H), 3.59 (s, 3H), 4.50-4.56 (m, 1H), 7.32-7.42 (m, 6H), 7.59-7.66 (m, 4H).

B. (trans)-3-((tert-Butyldiphenylsilyl)oxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-((tert-butyldiphenylsilyl)oxy)cyclobutanecarboxylate (Intermediate 129A) (3.00 g, 1.84 mmol) in THF (40 mL) was added LiOH hydrate (1.03 g, 24.4 mmol) in water (20 mL). After stirring overnight, the reaction was made acidic with the addition of 1 N aqueous HCl, and the mixture was extracted with EtOAc (4×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (2.80 g, 97%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ 1.01 (s, 9H), 2.28-2.42 (m, 4H), 2.93-3.01 (m, 1H), 4.48-4.56 (m, 1H), 7.32-7.42 (m, 6H), 7.58-7.62 (m, 4H); LC-MS (LC-ES) M−H=353.

C. (trans)-3-((tert-Butyldiphenylsilyl)oxy)-N-(thiazol-2-yl)cyclobutanecarboxamide

To a DMF (50 mL) solution of (trans)-3-((tert-butyldiphenylsilyl)oxy)cyclobutanecarboxylic acid (Intermediate 129B) (2.00 g, 5.64 mmol) was added HATU (2.68 g, 5.64 mmol) and N,N-diisopropylethylamine (2.96 mL, 16.9 mmol). After 5 minutes, thiazol-2-amine (706 mg, 7.05 mmol) was added, and the mixture was stirred for 6.5 h, poured into water, and extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. This residue was purified on silica gel, eluting with 0%-65% EtOAc in hexanes to give the title compound (1.92 g, 78%) as a white foam. 1 H NMR (400 MHz, CDCl 3 ) δ 1.03 (s, 9H), 2.38-2.46 (m, 2H), 2.52-2.60 (m, 2H), 3.12-3.20 (m, 1H), 4.61-4.68 (m, 1H), 6.96 (d, J=4 Hz, 1H), 7.33-7.44 (m, 7H), 7.61-7.65 (m, 4H), 10.90 (s, 1H); LC-MS (LC-ES) M+H=437.

D. (trans)-3-Hydroxy-N-(thiazol-2-yl)cyclobutanecarboxamide

To a THF solution (25 mL) of (trans)-3-((tert-butyldiphenylsilyhoxy)-N-(thiazol-2-yl)cyclobutanecarboxamide (Intermediate 129C) (1.92 g, 4.40 mmol) at 0° C. was added 1 M TBAF in THF (22.0 mL, 22.0 mmol). The reaction was allowed to warm to room temperature. After stirring overnight, the reaction was concentrated, and saturated aqueous NaHCO 3 solution (30 mL) was added. This mixture was extracted EtOAc (6×), and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel, eluting with 0%-75% EtOAc: EtOH (3:1) in hexanes to give the title compound (1.92 g, 78%) as a white solid. 1 H NMR (CDCl 3 ) δ 1.90-1.95 (m, 1H), 2.26-2.35 (m, 2H), 2.68-2.74 (m, 2H), 3.18-3.26 (m, 1H), 4.62-4.70 (m, 1H), 7.00 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 11.20 (s, 1H); LC-MS (LC-ES) M+H=199.

Intermediate 130: (trans)-3-(2,3-Diaminophenoxy)-N-(thiazol-2-yl)cyclobutanecarboxamide

A. 1-Azido-3-fluoro-2-nitrobenzene

To a solution of 1,3-difluoro-2-nitrobenzene (4.80 g, 30.2 mmol) in DMSO (35 mL) was added sodium azide (2.26 g, 34.7 mmol). After stirring overnight, the reaction was diluted with EtOAc (150 mL), washed with water (2×150 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound (5.40 g, 98%) as a pale yellow solid. 1 H NMR (CDCl 3 ) δ 6.99-7.11 (m, 2H), 7.46-7.52 (m, 1H).

B. (trans)-3-(3-Azido-2-nitrophenoxy)-N-(thiazol-2-yl)cyclobutanecarboxamide

To a solution of (trans)-3-hydroxy-N-(thiazol-2-yl)cyclobutanecarboxamide (Intermediate 129) (105 mg, 0.527 mmol) in THF (2 mL) was added a 60% dispersion of NaH in mineral oil (39 mg, 0.97 mmol). After 40 min, the reaction was cooled to −78° C., and 1-azido-3-fluoro-2-nitrobenzene (Intermediate 130A) (80 mg, 0.44 mmol) in THF (2.0 mL) was added. The mixture was allowed to warm to room temperature over 2 h and was quenched with saturated aqueous NH 4 Cl solution. The mixture was extracted with EtOAc (3×), and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel, eluting with 0%-100% EtOAc: EtOH (3:1) in hexanes to give the title compound (30 mg, 19%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 2.49-2.57 (m, 2H), 2.80-2.89 (m, 2H), 3.31-3.39 (m, 1H), 5.04-5.11 (m, 1H), 6.63-6.66 (m, 1H), 6.84-6.86 (m, 1H), 7.04-7.06 (m, 1H), 7.35-7.39 (m, 1H), 7.44-7.46 (m, 1H), 11.20 (s, 1H); LC-MS (LC-ES) M+H=361.

C. (trans)-3-(2,3-Diaminophenoxy)-N-(thiazol-2-yl)cyclobutanecarboxamide

To a MeOH solution (4 mL) containing 10% Pd/C (12 mg, 0.011 mmol) was added (trans)-3-(3-azido-2-nitrophenoxy)-N-(thiazol-2-yl)cyclobutanecarboxamide (Intermediate 130B) (27 mg, 0.075 mmol). The flask was then evacuated under vacuum and refilled with hydrogen via a balloon. The reaction was stirred under 1 atmosphere of hydrogen 5 h, filtered through a syringe filter and concentrated to give the title compound (27 mg, quantitative) as a glass. LC-MS (LC-ES) M+H=305.

Intermediate 131: (trans)-3-(Imidazo[1,2-a]pyridin-8-yloxy)cyclobutanecarboxylic acid

A. (trans)-Methyl 3-(imidazo[1,2-a]pyridin-8-yloxy)cyclobutanecarboxylate

Triphenylphosphine (293 mg, 1.12 mmol) was added to a solution of imidazo[1,2-a]pyridin-8-ol (125 mg, 0.932 mmol) in tetrahydrofuran (4 mL). The reaction mixture was cooled to 0° C., and (cis)-methyl 3-hydroxycyclobutanecarboxylate (133 mg, 1.03 mmol) was added, followed by DIAD (0.22 mL, 1.1 mmol). After 10 min, the reaction mixture was warmed to room temperature, stirred for 3 days and diluted with water and EtOAc. The mixture was partitioned, and the aqueous layer was extracted with EtOAc (2×). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a 0%-100% EtOAc: EtOH (3:1) in hexanes to give the title compound (110 mg, 48%). 1 H NMR (400 MHz, CDCl 3 ) δ 2.61-2.70 (m, 2H), 2.75-2.82 (m, 2H), 3.18-3.27 (m, 1H), 3.72 (s, 3H), 5.02-5.10 (m, 1H), 6.23-6.26 (m, 1H), 6.60-6.66 (m, 1H), 7.53-7.56 (m, 2H), 7.73-7.76 (m, 1H); LC-MS (LC-ES) M+H=248.

B. (trans)-3-(Imidazo[1,2-a]pyridin-8-yloxy)cyclobutanecarboxylic acid

To a solution of (trans)-methyl 3-(imidazo[1,2-a]pyridin-8-yloxy)cyclobutanecarboxylate (Intermediate 131A) (80 mg, 0.33 mmol) in THF (4 mL) was added LiOH monohydrate (34 mg, 0.81 mmol) in water (2 mL). After stirring overnight, the reaction was adjusted to pH=4 with the addition of saturated aqueous citric acid, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (72 mg, 96%) as a tacky white solid. LC-MS (LC-ES) M+H=233.

Intermediate 132: 4-(Azetidin-3-yloxy)benzo[d]isothiazole hydrochloride

A. 2-(Benzylthio)-6-methoxybenzaldehyde

To a stirred, cooled (0° C.) suspension of sodium tert-butoxide (750 mg, 7.80 mmol) in THF (10 mL) was added benzyl mercaptan (0.80 mL, 6.8 mmol). After 30 minutes, 2-fluoro-6-methoxybenzaldehyde (1.00 g, 6.49 mmol) in THF (2 mL) was added dropwise. The mixture was warmed to room temperature and after 1 h poured into water (30 mL). The resulting precipitate was stirred for 5 minutes, collected via vacuum filtration and washed with water (10 mL) and Et 2 O (10 mL) and dried in vacuo to give the title compound (1.71 g, quantitative) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.91 (s, 3H), 4.21 (s, 2H), 6.98 (d, J=9 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 7.29 (d, J=7 Hz, 1H), 7.32-7.38 (m, 2H), 7.40-7.47 (m, 2H), 7.56 (t, J=8 Hz, 1H), 10.45 (s, 1H); LC-MS (LC-ES) M+H=259.

B. 4-Methoxybenzo[d]isothiazole

A mixture of 2-(benzylthio)-6-methoxybenzaldehyde (Intermediate 132A) (1.71 g, 6.62 mmol) and thioanisole (1.60 mL, 13.5 mmol) in acetonitrile (15 mL) and water (15 mL) was stirred for 30 minutes. To this mixture was added hydroxylamine-O-sulfonic acid (1.15 g, 10.2 mmol). After 2 h, the mixture was quenched with saturated aqueous NaHCO 3 (40 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 0%-10% EtOAc in hexanes gradient to give the title compound (682 mg, 62%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 4.00 (s, 3H), 6.99 (d, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 9.07 (d, J=1 Hz, 1H); LC-MS (LC-ES) M+H=166.

C. Benzo[d]isothiazol-4-ol

A mixture of 4-methoxybenzo[d]isothiazole (Intermediate 132B) (674 mg, 4.08 mmol) and pyridine hydrochloride (4.30 g, 37.2 mmol) was heated to 195° C. After 5 h, the reaction was cooled and diluted with water and EtOAc and stirred overnight. The mixture was poured into 1 N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and filtered. The residue was purified on silica gel eluting with a 0%-25% EtOAc in hexanes gradient to give the title compound (480 mg, 78%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 6.81 (d, J=8 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 9.06 (d, J=1 Hz, 1H), 10.72 (s, 1H); LC-MS (LC-ES) M+H=152.

D. tert-Butyl 3-(benzo[d]isothiazol-4-yloxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (260 mg, 1.04 mmol) and benzo[d]isothiazol-4-ol (Intermediate 132C) (150 mg, 0.992 mmol) in DMF (4 mL) was added cesium carbonate (360 mg, 1.11 mmol). The mixture was heated to 80° C. overnight, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining material was purified on silica gel eluting with a 0%-40% EtOAc-hexanes gradient to give the title compound (178 mg, 69%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.40 (s, 9H), 3.95 (d, J=7 Hz, 2H), 4.35-4.46 (m, 2H), 5.18-5.27 (m, 1H), 6.73 (d, J=8 Hz, 1H), 7.53 (t, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 9.13 (s, 1H); LC-MS (LC-ES) M+H=307.

E. 4-(Azetidin-3-yloxy)benzo[d]isothiazole hydrochloride

To neat tert-butyl 3-(benzo[d]isothiazol-4-yloxy)azetidine-1-carboxylate (Intermediate 132D) (177 mg, 0.578 mmol) was added 4 N HCl in dioxane (3.0 mL, 12 mmol). After 2.5 h, the mixture was diluted with diethyl ether, and the resulting solid was collected by filtration to give the title compound as a white solid (138 mg, 98%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 4.05-4.19 (m, 2H), 4.45-4.60 (m, 2H), 5.32 (t, J=5 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 9.15 (s, 1H); LC-MS (LC-ES) M+H=207.

Intermediate 133: 4-(Azetidin-3-yloxy)-2-methylbenzo[d]thiazole hydrochloride

A. 2-Fluoro-6-methoxyaniline

To an EtOH solution (400 mL) containing 10% Pd/C (7.46 g, 70.1 mmol) in a Parr vessel was added 1-fluoro-3-methoxy-2-nitrobenzene (40.0 g, 234 mmol). The vessel was evacuated under vacuum and refilled with hydrogen (50 psi). The reaction was shaken 5 h, filtered through Celite® and concentrated to give the title compound (30.0 g, 83%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 3.75 (br s, 2H), 3.86 (s, 3H), 6.58-6.71 (m, 3H); LC-MS (LC-ES) M+H=142.

B. N-(2-Fluoro-6-methoxyphenyl)acetamide

To a suspension of 2-fluoro-6-methoxyaniline (Intermediate 133A) (30.0 g, 193 mmol) in acetic anhydride (21.9 mL, 232 mmol) and DCM (200 mL) was added triethylamine (40.4 mL, 290 mmol), dropwise. After 12 h, the reaction mixture was concentrated, and the residue taken up in saturated aqueous sodium bicarbonate (250 mL). The resulting solid was collected by filtration to give the title compound (25.0 g, 65%). LC-MS (LC-ES) peak at T=1.29 min; M+H=184.

C. N-(2-Fluoro-6-methoxyphenyl)ethanethioamide

To a solution of N-(2-fluoro-6-methoxyphenyl)acetamide (Intermediate 133B) (5.00 g, 24.8 mmol) in toluene (100 mL) was added Lawesson's reagent (5.02 g, 12.4 mmol), and the reaction was heated to 120° C. After 3 h, the reaction mixture was evaporated under reduced pressure and the residue triturated with pentane (50 mL) to give the title compound (5.20 g, 77%) as an off white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 2.77 (s, 3H), 3.90 (s, 3H), 6.69-6.90 (m, 3H); LC-MS (LC-ES) M+H=200.

D. 4-Methoxy-2-methylbenzo[d]thiazole

To a solution of N-(2-fluoro-6-methoxyphenyl)ethanethioamide (Intermediate 133C) (5.20 g, 19.1 mmol) in DMF (50 mL) was added a 60% dispersion of NaH in mineral oil (762 mg, 19.1 mmol). The reaction was heated to 80° C. After 12 h, the mixture was cooled to room temperature and quenched with water (200 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound (4.00 g, 86%) as a yellow solid. LC-MS (LC-ES) M+H=180.

E. 2-Methylbenzo[d]thiazol-4-ol

A mixture of 4-methoxy-2-methylbenzo[d]thiazole (Intermediate 133D) (4.00 g, 16.4 mmol) and pyridine hydrochloride (18.90 g, 164 mmol) was heated to 150° C. After 1 h, the reaction was cooled and diluted with ice water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound (3.00 g, 75%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 2.81 (s, 3H), 6.94-6.98 (m, 1H), 7.23-7.28 (m, 1H), 7.31-7.36 (m, 1H); LC-MS (LC-ES) M+H=166.

F. tert-Butyl 3-((2-methylbenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (3.39 g, 13.5 mmol) and 2-methylbenzo[d]thiazol-4-ol (Intermediate 133E) (3.00 g, 12.3 mmol) in DMF (15 mL) was added cesium carbonate (5.19 g, 15.9 mmol). The mixture was heated to 80° C. for 3 h, poured into ice water (100 mL) and extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel eluting with a 0%-15% EtOAc-hexanes gradient to give the title compound (800 mg, 20%) as an off white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.45 (s, 9H), 2.86 (s, 3H), 4.20-4.28 (m, 2H), 4.33-4.40 (m, 2H), 5.09-5.19 (m, 1H), 6.57-6.61 (m, 1H), 7.21-7.28 (m, 1H), 7.43-7.49 (m, 1H); LC-MS (LC-ES) M+H=321.

G. 4-(Azetidin-3-yloxy)-2-methylbenzo[d]thiazole hydrochloride

To tert-butyl 3-((2-methylbenzo[d]thiazol-4-yl)oxy)azetidine-1-carboxylate (Intermediate 133F) (800 mg, 2.49 mmol) in MeOH (8 mL) was added 4 N HCl in dioxane (2.49 mL, 9.96 mmol). After 1 h, the mixture was concentrated, and the residue was triturated with diethyl ether (20 mL) to give the title compound as an off white solid (610 mg, 94%). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.79 (s, 3H), 4.05-4.15 (m, 2H), 4.43-4.52 (m, 2H), 5.26-5.35 (m, 1H), 6.86-6.89 (m, 1H), 7.29-7.35 (m, 1H), 7.63-7.70 (m, 1H), 9.49 (br s, 2H); LC-MS (LC-ES) M+H=221.

Intermediate 134: (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclobutanecarboxamide

A. 5-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl-1H-pyrazole

To a stirred, cooled (0° C.) solution of 5-nitro-1H-pyrazole (1.00 g, 8.84 mmol) in N,N-dimethylformamide (5 mL) was slowly added potassium carbonate (2.44 g, 17.1 mmol), followed by (2-(chloromethoxy)ethyl)trimethylsilane (1.77 g, 10.6 mmol). The progress of the reaction was monitored by TLC (silica, 30% EtOAc in hexane). Upon completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate, 3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound (560 mg, 17.5%). This material was used without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 0.08-0.01 (m, 9H), 0.84-0.96 (m, 2H), 3.54-3.64 (m, 2H), 5.43 (s, 2H), 6.96 (d, J=3 Hz, 1H) 7.60-7.73 (m, 1H); LC-MS (LC-ES) M+H=244.

B. 1-((2-(Trimethylsilyl)ethoxy)methyl-1H-pyrazol-5-amine

To a solution of 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (560 mg, 2.30 mmol) in ethyl acetate (20 mL) was added palladium on carbon (245 mg). The mixture was stirred under a hydrogen atmosphere for 12 hours, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was diluted with dichloromethane, pre-adsorbed onto silica gel, and chromatographed on silica gel, eluting with a 10-20% ethyl acetate in hexanes gradient to give the title compound (250 mg, 47%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 0.09-0.02 (m, 9H), 0.80-0.99 (m, 2H), 3.47-3.63 (m, 2H), 3.86 (br s, 2H), 5.35 (s, 2H), 7.14-7.36 (m, 2H); LC-MS (LC-ES) M+H=214.

C. (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclobutanecarboxamide

To a stirred, cooled (0° C.) solution of (trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid (Intermediate 25) (150 mg, 0.602 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.315 mL, 1.805 mmol) slowly dropwise, followed by 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (128 mg, 0.602 mmol) and then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (458 mg, 1.203 mmol). The mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was diluted with cold ice water (10 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound (250 mg, 83%) as a gummy oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.06-0.08 (m, 9H), 0.76-0.95 (m, 2H), 2.40-2.54 (m, 2H), 2.69-2.81 (m, 2H), 3.30-3.42 (m, 1H), 3.51-3.60 (m, 2H), 5.12-5.21 (m, 1H), 5.79 (s, 2H), 6.67 (d, J=2 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.41-7.51 (m, 1H), 7.73 (d, J=8 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 9.30 (s, 1H), 10.58 (br s, 1H); LC-MS (LC-ES) M+H=445.

Intermediate 135: (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclobutanecarboxamide

A. 3-Cyclopropyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a stirred, cooled (0° C.) solution of 3-cyclopropyl-5-nitro-1H-pyrazole (600 mg, 3.92 mmol) in tetrahydrofuran (10 mL) was added potassium carbonate (1.08 g, 7.84 mmol), followed by (2-(chloromethoxy)ethyl)trimethylsilane (719 mg, 4.31 mmol). The mixture was warmed to room temperature and stirred for 3 hours. Water (10 mL) was added to the mixture, followed by extraction with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography, eluting with a 4:1 ethyl acetate in hexanes gradient to give the title compound (500 mg, 45%). 1 H NMR (400 MHz, CDCl 3 ) δ −0.08-0.03 (m, 9H), 0.75-0.80 (m, 2H), 0.84-0.95 (m, 2H), 0.94-1.02 (m, 2H), 1.83-2.05 (m, 1H), 3.55-3.65 (m, 2H), 5.59 (s, 1H), 5.78 (s, 1H), 6.48 (s, 0.4H), 6.78 (s, 0.6H); LC-MS (LC-ES) M+H=284.

B. 3-Cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-amine

To a solution of 3-cyclopropyl-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (500 mg, 0.998 mmol) in tetrahydrofuran (10 mL) was added palladium on carbon (500 mg). The mixture was stirred under a hydrogen atmosphere for 17 hours, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography, eluting with a 10-15% ethyl acetate in hexanes gradient to give the title compound (150 mg, 54%). 1 H NMR (400 MHz, CDCl 3 ) δ −0.02 (s, 9H), 0.62-0.68 (m, 2H), 0.85-1.00 (m, 4H), 1.73-1.91 (m, 1H), 3.51-3.71 (m, 4H), 5.27 (s, 1H), 5.32 (s, 2H); LC-MS (LC-ES) M+H=254.

C. (trans)-3-(Benzo[d]thiazol-4-yloxy)-N-(3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclobutanecarboxamide

To a stirred, cooled (0° C.) solution of (trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid (Intermediate 25) (150 mg, 0.602 mmol) in N,N-dimethylformamide (10 mL) was added 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (167 mg, 0.66 mmol), followed by N,N-diisopropylethylamine (0.312 mL, 1.79 mmol), and then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (453 mg, 1.19 mmol). The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with cold ice water (10 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography, eluting with a 10-15% ethyl acetate in hexanes gradient to give the title compound (220 mg, 64%). 1 H NMR (400 MHz, CDCl 3 ) δ 0.09 (s, 9H), 0.69-0.83 (m, 2H), 0.86-1.06 (m, 2H), 1.25-1.34 (m, 3H), 2.61-2.77 (m, 2H), 2.85-2.92 (m, 2H), 3.14-3.28 (m, 1H), 3.54-3.65 (m, 2H), 5.20-5.28 (m, 1H), 5.40 (s, 2H), 6.41 (s, 1H), 6.78 (d, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.64 (s, 1H), 8.93 (s, 1H); LC-MS (LC-ES) M+H=485.

Intermediate 136: 1-(4-Aminopiperidin-1-yl)-2-hydroxy-2-methylpropan-1-one

A. Benzyl (1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)carbamate

Benzyl piperidin-4-ylcarbamate (512 mg, 2.18 mmol) was added to 2-hydroxy-2-methylpropanoic acid (227 mg, 2.18 mmol) in 1,4-dioxane (11 mL) at room temperature. N,N-diisopropylethylamine (1.14 mL, 6.55 mmol) was added to the mixture and the stirring was continued for five minutes. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (830 mg, 2.18 mmol) was added and the reaction mixture was stirred for sixteen hours. The reaction mixture was poured into saturated sodium bicarbonate, extracted with ethyl acetate (3×), dried over magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by silica gel chromatography, eluting with ethyl acetate:hexanes (1:1 to 0:1) to give the title compound (315 mg, 43% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.28 (s, 6H), 1.28-1.36 (m, 2H), 1.74 (d, J=12 Hz, 2H), 2.60-3.24 (m, 2H), 3.48-3.62 (m, 1H), 4.10-4.70 (m, 2H), 5.00 (s, 2H), 5.33 (s, 1H), 7.26-7.40 (m, 6H); LC-MS (LC-ES) M+H=321.

B. 1-(4-Aminopiperidin-1-yl)-2-hydroxy-2-methylpropan-1-one

Palladium on carbon (0.105 g, 0.098 mmol) was added to benzyl (1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)carbamate (0.315 g, 0.984 mmol) in methanol (3.3 mL) under a nitrogen atmosphere. The reaction vessel was fitted with a hydrogen balloon and the vessel was repeatedly evacuated and purged with hydrogen, then stirred for sixteen hours. The vessel was repeatedly evacuated and purged with nitrogen, filtered through Celite®, and concentrated to give the title compound (0.175 g, 91% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.00-1.80 (m, 2H), 1.29 (s, 6H), 1.54 (br s, 2H), 1.67 (d, J=12 Hz, 2H), 2.76 (p, J=5 Hz, 1H), 2.54-3.18 (m, 2H), 4.02-4.72 (m, 2H), 5.28 (s, 1H); LC-MS (LC-ES) M+H=187.

Intermediate 137: (2S,3S)-tert-Butyl 3-(benzo[d]thiazol-4-yloxy)-2-methylazetidine-1-carboxylate

and

Intermediate 138: (2R,3R)-tert-Butyl 3-(benzo[d]thiazol-4-yloxy)-2-methylazetidine-1-carboxylate

To a stirred solution of tert-butyl 2-methyl-3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 99A) (1.40 g, 5.28 mmol) and benzo[d]thiazol-4-ol (0.800 g, 5.29 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.90 g, 5.83 mmol). The mixture was heated to 100° C. and stirred overnight. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure. The remaining material was dissolved in a minimal amount of dichloromethane and chromatographed on silica gel, eluting with a 0%-50% ethyl acetate to hexanes gradient to give the desired product (1.20 g, 71%) as a mixture of diastereomers. The isomers were separated by chiral SFC on an IC column (30 mm×250 mm×5 um column with 45% IPA. Intermediate 137 (29 mg, 1.7%) was obtained as a sticky foam. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.31 (d, J=6 Hz, 3H), 1.41 (s, 9H), 3.85 (br s, 1H), 4.30 (br s, 1H), 4.68 (t, J=6 Hz, 1H), 5.27 (td, J=7, 4 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 9.30 (s, 1H); LC-MS (LC-ES) M+H=321. Intermediate 138 (18 mg, 1.1%) was obtained as a sticky foam. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.31 (d, J=6 Hz, 3H) 1.41 (s, 9H) 3.85 (br s, 1H) 4.30 (br s, 1H) 4.68 (t, J=6 Hz, 1H) 5.27 (td, J=7, 4 Hz, 1H) 6.92 (d, J=8 Hz, 1H) 7.40 (t, J=8 Hz, 1H) 7.75 (d, J=8 Hz, 1H) 9.30 (s, 1H); LC-MS (LC-ES) M+H=321.

Intermediate 139: 4-(((2S,3S)-2-Methylazetidin-3-yl)oxy)benzo[d]thiazole hydrochloride

To a stirred solution of (2S,3S)-tert-butyl 3-(benzo[d]thiazol-4-yloxy)-2-methylazetidine-1-carboxylate (Intermediate 137) (29 mg, 0.091 mmol) in methanol (0.5 mL) was added 4N hydrochloric acid (0.5 mL, 2.00 mmol) in dioxane. After stirring for 3 hours, solvent was removed under reduced pressure and the remaining material was placed in vacuo to give the title compound. This material was used without further characterization. LC-MS (LC-ES) M+H=221.

Intermediate 140: 4-(((2R,3R)-2-Methylazetidin-3-yl)oxy)benzo[d]thiazole hydrochloride

To a stirred solution of (2R,3R)-tert-butyl 3-(benzo[d]thiazol-4-yloxy)-2-methylazetidine-1-carboxylate (Intermediate 138) (18 mg, 0.056 mmol) in methanol (0.5 mL) was added 4N hydrochloric acid (0.5 mL, 2.00 mmol) in dioxane. After stirring for 3 hours, solvent was removed under reduced pressure and the remaining material was placed in vacuo to give the title compound. This material was used without further characterization. LC-MS (LC-ES) M+H=221.

Intermediate 141: 4-Nitrophenyl (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)carbamate

A mixture of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (100 mg, 0.729 mmol) and N,N-diisopropylethylamine (0.125 mL, 0.716 mmol) dissolved in dichloromethane (3 mL) was added to a stirred, cooled (0° C.) solution of 4-nitrophenyl chloroformate (150 mg, 0.744 mmol) in dichloromethane (5 mL) dropwise over 10 minutes. The mixture was stirred for 1.5 hours and then partitioned between water and ethyl acetate. The biphasic mixture was filtered to remove insoluble material and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine and the layers were separated. Solid material began to precipitate. Solvent was removed under reduced pressure and the remaining solid material was triturated with 1:1 ethyl acetate:hexane, collected via vacuum filtration, and dried in vacuo to give the title compound (117 mg, 53%) as a pale yellow solid. This material was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.54-0.61 (m, 2H), 0.75-0.82 (m, 2H), 1.71-1.80 (m, 1H), 3.59 (s, 3H), 5.86 (s, 1H), 7.75 (d, J=9 Hz, 2H), 8.38-8.43 (m, 2H), 9.34 (br s, 1H); LC-MS (LC-ES) M+H=302.

Intermediate 142: N1-(Pyrimidin-2-yl)bicyclo[1.1.1]pentane-1,3-diamine hydrochloride

A. tert-Butyl (3-(pyrimidin-2-ylamino)bicyclo[1.1.1]pentan-1-yl)carbamate

To a N,N-dimethylformamide (2 mL) solution of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (140 mg, 0.706 mmol) and 2-chloropyrimidine (81 mg, 0.706 mmol) in a vial was added N,N-diisopropylethylamine (0.247 mL, 1.412 mmol). The vial was sealed and heated to 125° C. in an oil bath for 1.5 hours. After cooling to room temperature, the mixture was diluted with methanol and purified by reverse HPLC, eluting with a acetonitrile:water (1% ammonium hydroxide modifier) gradient to give the title compound (21 mg, 11%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.48 (s, 9H), 2.24-2.52 (m, 6H), 5.06 (br s, 1H), 5.68-6.03 (m, 1H), 6.59 (t, J=5 Hz, 1H), 8.29 (d, J=5 Hz, 2H); LC-MS (LC-ES) M+H=277.

B. N1-(Pyrimidin-2-yl)bicyclo[1.1.1]pentane-1,3-diamine hydrochloride

To a stirred solution of tert-butyl (3-(pyrimidin-2-ylamino)bicyclo[1.1.1]pentan-1-yl)carbamate (20 mg, 0.072 mmol) in dichloromethane (2 mL) was added 4M hydrochloric acid in dioxane (1 mL, 4.00 mmol). After stirring for 5 hours, LCMS analysis of the mixture showed the reaction was incomplete. Additional 4M hydrochloric acid in dioxane was added. Solvent was removed under reduced pressure to afford the title compound (18 mg, 117%) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ 2.59 (s, 6H), 7.13 (br s, 1H), 8.68 (br s, 2H); LC-MS (LC-ES) M+H=177.

Intermediate 143: 2-(3-Aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol hydrochloride

A. tert-Butyl (3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

To a stirred, cooled (0° C.) solution of ethyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (200 mg, 0.829 mmol) in tetrahydrofuran (3 mL) was slowly added 3M methylmagnesium bromide in diethyl ether (0.9 mL, 2.70 mmol). After stirring for ˜10 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was recooled to 0° C. and additional 3M methylmagnesium bromide in diethyl ether (0.9 mL, 2.70 mmol) was slowly added. The mixture was allowed to warm to room temperature, stirred for 30 minutes and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure to give the title compound (176 mg, 88%) as a colorless oil. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.03 (s, 6H), 1.37 (s, 9H), 1.70 (s, 6H), 4.11 (s, 1H), 7.38 (br s, 1H).

B. 2-(3-Aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol hydrochloride

To a stirred solution of tert-butyl (3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (170 mg, 0.704 mmol) in methanol (2.5 mL) was added 4M hydrochloric acid in dioxane (0.88 mL, 3.52 mmol). The mixture was stirred overnight. Solvent was removed under reduced pressure and the remaining colorless oil became a solid upon scratching to give the title compound (144 mg, 115% yield). 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.05 (s, 6H), 1.80 (s, 6H), 3.17 (s, 1H), 8.72 (br s, 3H).

Intermediate 144: 4-(Aminocuban-1-yl)propan-2-ol hydrochloride

A. Methyl 4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate

To a stirred solution of 4-(methoxycarbonyl)cubane-1-carboxylic acid (500 mg, 2.42 mmol) in tert-butanol (10 mL) was added triethylamine (1.40 mL, 10.0 mmol), followed by diphenyl phosphoryl azide (0.80 mL, 3.71 mmol). The mixture was stirred for 1 hour at room temperature and then heated to reflux while stirring overnight. After cooling to room temperature, the mixture was evaporated under reduced pressure. The remaining residue was dissolved in ethyl acetate, washed with saturated brine (3×), dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure. The remaining solid was triturated with ethyl acetate-hexane, collected by vacuum filtration and discarded. The filtrate was evaporated under reduced pressure. The remaining material was chromatographed on silica gel, eluting with a 5%-25% ethanol in hexanes gradient to give the title compound (134 mg, 20%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.39 (s, 9H), 3.62 (s, 3H), 3.98 (br s, 6H).

B. tert-Butyl 4-(2-hydroxypropan-2-yl)cuban-1-yl)carbamate

To a stirred, cooled (0° C.) solution of methyl-4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate (132 mg, 0.476 mmol) in tetrahydrofuran (5 mL) was added 3M methylmagnesium bromide (0.7 mL, 2.10 mmol) in diethyl ether. The mixture was allowed to warm to room temperature while stirring overnight. TLC analysis (silica gel, 1:1 ethyl acetate-hexane, PMA stain) of the mixture showed 2 major spots. The mixture was re-cooled to 0° C. and additional 3M methylmagnesium bromide (0.35 mL, 1.05 mmol) in diethyl ether was added dropwise. The mixture was allowed to warm to room temperature while stirring for 6 hours. The mixture was quenched with saturated aqueous ammonium chloride, poured into water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure. The remaining material dissolved in a minimal amount of dichloromethane and chromatographed on silica gel, eluting with a 0%-100% ethyl acetate in hexanes to give the title compound (58 mg, 44%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.99 (s, 6H), 1.38 (s, 9H), 3.62 (br s, 3H), 3.73 (br s, 3H), 4.07 (s, 1H).

C. 4-(Aminocuban-1-yl)propan-2-ol hydrochloride

To a stirred, cooled (0° C.) solution of tert-butyl 4-(2-hydroxypropan-2-yl)cuban-1-yl)carbamate (58 mg, 0.209 mmol) in methanol (1 mL) was added 4M hydrochloric acid in dioxane (0.5 mL, 2.000 mmol). The mixture was allowed to warm to room temperature while stirring for 4 hours. Solvent was removed under reduced pressure and the remaining material was triturated with diethyl ether, evaporated under reduced pressure and triturated with hexane. Solvent was removed under reduced pressure and the remaining material was placed in vacuo to give the title compound (45 mg, 101%) as a tan solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 0.62 (s, 6H), 2.61 (t, J=5 Hz, 1H), 3.00 (dd, J=7, 5 Hz, 2H), 3.30-3.38 (m, 3H), 5.30 (s, 1H), 8.50 (br s, 3H).

Intermediate 145: Ethyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate hydrochloride

A. tert-Butyl ethyl bicyclo[1.1.1]pentane-1,3-diyldicarbamate

To a stirred, cooled (0° C.) solution of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (200 mg, 1.01 mmol) in tetrahydrofuran (3.5 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.43 mmol), followed by ethyl chloroformate (0.11 mL, 1.15 mmol). After 5 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The resulting white suspension was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure to give the title compound (300 mg, 110%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.14 (t, J=7 Hz, 3H), 1.37 (s, 9H), 2.03 (s, 6H), 3.95 (q, J=7 Hz, 2H), 7.52 (br s, 1H), 7.78 (br s, 1H).

B. Ethyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate hydrochloride

4N Hydrochloric acid in dioxane (1.5 mL, 6.00 mmol) was added to tert-butyl ethyl bicyclo[1.1.1]pentane-1,3-diyldicarbamate (300 mg, 1.11 mmol). The resulting suspension was stirred for 1.75 hours. Solvent was removed under reduced pressure and the remaining material was placed in vacuo to give the title compound (225 mg, 98%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.15 (t, J=7 Hz, 3H), 2.14 (s, 6H), 3.98 (q, J=7 Hz, 2H), 8.76 (br s, 3H).

Intermediate 146: Phenyl (5-methyl-1,3,4-thiadiazol-2-yl)carbamate

To a stirred, cooled (5° C.) solution of 5-methyl-1,3,4-thiadiazol-2-amine (100 mg, 0.868 mmol) in tetrahydrofuran (7 mL) was added pyridine (0.28 mL, 3.47 mmol). The mixture was stirred for 10 minutes and then phenyl chloroformate (204 mg, 1.30 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with diethyl ether (10 mL) and stirred for 10 minutes. The resulting solid was collected by vacuum filtration, washed with diethyl ether and dried to give the title compound (185 mg, 83%) as an off-white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.61 (s, 3H), 7.20-7.34 (m, 3H), 7.42-7.51 (m, 2H), 12.45 (br s, 1H); LC-MS (LC-ES) M+H=236.

Intermediate 147: Phenyl (1-methyl-1H-pyrazol-3-yl)carbamate

To a stirred, cooled (0° C.) solution of 1-methyl-1H-pyrazol-3-amine (1.00 g, 10.30 mmol) in tetrahydrofuran (20 mL) was added pyridine (3.33 mL, 41.2 mmol). The mixture was stirred for 5 minutes and then phenyl chloroformate (2.42 g, 15.5 mmol) was added. The mixture was warmed to room temperature and stirred for 5 minutes. Solvent was removed under reduced pressure to give the title compound (500 mg, 13%) in 59% purity. This material was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.74 (s, 3H), 6.23 (s, 1H), 7.17 (d, J=8 Hz, 2H), 7.22-7.31 (m, 1H), 7.37-7.45 (m, 2H), 7.56 (s, 1H), 10.42 (br s, 1H); LC-MS (LC-ES) M+H=218.

Intermediate 148: Phenyl (5-methoxypyridin-3-yl)carbamate

To a stirred, cooled (0° C.) solution of 5-methoxypyridin-3-amine (100 mg, 0.806 mmol) in tetrahydrofuran (10 mL) was added pyridine (0.26 mL, 3.22 mmol). The mixture was stirred for 5 minutes and then phenyl chloroformate (189 mg, 1.21 mmol) was added. The mixture was warmed to room temperature and stirred for 3 hours. Solvent was removed under reduced pressure to give the title compound (120 mg, 45%) In 73% purity as a pink solid. This material was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.84 (s, 3H), 7.20-7.53 (m, 5H), 7.73 (s, 1H), 8.13 (d, J=2 Hz, 1H), 8.38 (d, J=2 Hz, 1H), 10.70 (br s, 1H); LC-MS (LC-ES) M+H=245.

Intermediate 149: Phenyl (1-methyl-1H-pyrazol-4-yl)carbamate

To a stirred, cooled (0° C.) solution of 1-methyl-1H-pyrazol-4-amine (100 mg, 1.03 mmol) in tetrahydrofuran (2 mL) was added pyridine (0.33 mL, 4.12 mmol). The mixture was stirred for 5 minutes and then phenyl chloroformate (177 mg, 1.13 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hours. Solvent was removed under reduced pressure to give the title compound (200 mg, 55%) in 62% purity. This material was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ ppm 3.79 (s, 3H), 7.14-7.20 (m, 2H), 7.25-7.37 (m, 4H), 7.46-7.53 (m, 1H), 9.98 (s, 1H); LC-MS (LC-ES) M+H=218.

Intermediate 150: Phenyl (1-ethyl-1H-tetrazol-5-yl)carbamate

To a stirred solution of 1-ethyl-1H-tetrazol-5-amine (250 mg, 2.21 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (611 mg, 4.42 mmol), followed by phenyl chloroformate (519 mg, 3.32 mmol). The mixture was stirred for 4 hours. The solid material was collected by vacuum filtration, washed with pentane, and dried to give the title compound (180 mg, 27%) in 77% purity as an off-white solid. This material was used without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 1.65 (t, J=7 Hz, 3H), 4.64 (q, J=7 Hz, 2H), 7.18-7.29 (m, 3H), 7.37-7.46 (m, 2H), 7.90 (br s, 1H); LC-MS (LC-ES) M+H=234.

Intermediate 151: Phenyl (5-isopropyl-1,3,4-oxadiazol-2-yl)carbamate

To a stirred cooled (0° C.) solution of 5-isopropyl-1,3,4-oxadiazol-2-amine (100 mg, 0.787 mmol) in tetrahydrofuran (8 mL) was added phenyl chloroformate (135 mg, 0.865 mmol) and pyridine (0.254 mL, 3.15 mmol). The mixture was warmed to room temperature and stirred for 4 hours. Solvent was removed under reduced pressure to give the title compound (180 mg, 32%) in 34% purity. This material was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.16-1.35 (m, 6H), 2.94-3.03 (m, 1H), 7.17 (t, J=8 Hz, 1H), 7.26-7.41 (m, 2H), 7.46-7.58 (m, 2H), 9.40 (s, 1H); LC-MS (LC-ES) M+H=248.

Intermediate 152: Phenyl (4-cyano-3-methyl-1H-pyrazol-5-yl)carbamate

To a stirred, cooled (0° C.) solution of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile (300 mg, 2.46 mmol) in tetrahydrofuran (10 mL) was added phenyl chloroformate (423 mg, 2.70 mmol) and pyridine (0.795 mL, 9.83 mmol). The mixture was warmed to room temperature and stirred for 4 hours. Solvent was removed under reduced pressure to give the title compound (245 mg, 11%) in 26% purity. This material was used without further purification. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 2.12 (s, 3H), 7.09-7.54 (m, 5H), 9.34 (brs, 1H), 13.15 (brs, 1H); LC-MS (LC-ES) M+H=243.

Intermediate 153: 4-((1-(((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)carbamoyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxylic acid

A. Methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate

To a stirred solution of methyl 4-amino-3-methoxybenzoate (2.00 g, 11.04 mmol) in methanol (25 mL) was added an intimated mixture of potassium thiocyanate (10.0 g, 103 mmol) and anhydrous copper(II) sulfate (8.00 g, 50.1 mmol) in one portion. The resulting black mixture was heated to reflux for 3 hours. The reaction suspension was filtered and the filter cake was washed with methanol. The filtrate was evaporated to dryness to give a dark colored solid. This material was redissolved in methanol, diluted with water, and heated to boiling until a clear solution formed. The mixture was allowed to cool to room temperature while standing overnight. The resulting solid was collected via vacuum filtration, washed with water, and dried in vacuo to give the title compound (1.26 g, 48%) as a yellow solid. The aqueous filtrate from the previous day contained solid material and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure and the remaining material was dried in vacuo to give the title compound (181 mg, 1.6%) as a yellow solid. The aqueous layer still contained solid. The solid was collected via vacuum filtration, washed with water and dried in vacuo to give additional title compound (988 mg, 9%) as a yellow solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.85 (s, 3H), 3.92 (s, 3H), 7.41 (s, 1H), 8.03 (br s, 1H), 8.24 (br s, 2H); LC-MS (LC-ES) M+H=239.

B. Methyl 4-methoxybenzo[d]thiazole-6-carboxylate

To a stirred suspension of methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate (200 mg, 0.839 mmol) in 1,4-dioxane (3 mL) was added isoamyl nitrite (0.60 mL, 4.46 mmol). The mixture was stirred for 6 hours, poured into water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure. The remaining material was dissolved in a minimal amount of dichloromethane and chromatographed on silica gel, eluting with a 5%-40% ethyl acetate in hexanes gradient to give the title compound (62 mg, 33%) as a yellow solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.91 (s, 3H), 4.03 (s, 3H), 7.53 (d, J=1 Hz, 1H), 8.43 (d, J=1 Hz, 1H), 9.47 (s, 1H); LC-MS (LC-ES) M+H=224.

C. Methyl 4-hydroxybenzo[d]thiazole-6-carboxylate

To a stirred, cooled (−78° C.) solution of methyl 4-methoxybenzo[d]thiazole-6-carboxylate (775 mg, 3.47 mmol) in dichloromethane (20 mL) was added 1M boron tribromide (16.5 mL, 16.5 mmol) in dichloromethane dropwise. The mixture was stirred for 3 hours at −78° C. and then allowed to warm to room temperature, while stirring overnight. Solvent was removed under reduced pressure. Methanol (20 mL) was added dropwise to the residue with stirring for 5 minutes and then evaporated under reduced pressure. The remaining material was triturated with water and the solid was collected via vacuum filtration, washed with water, and dried in vacuo to give the title compound (157 mg, 22%) as a yellow solid. Additional solid was obtained from the filtrate and recrystallized from methanol, while standing for 3 days, to give additional title compound (44 mg, 6%) as a yellow solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 3.88 (s, 3H), 7.47 (d, J=2 Hz, 1H), 8.24 (d, J=2 Hz, 1H), 9.42 (s, 1H); LC-MS (LC-ES) M+H=210.

D. Methyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxylate

To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (Intermediate 1) (265 mg, 1.055 mmol) and methyl 4-hydroxybenzo[d]thiazole-6-carboxylate (198 mg, 0.946 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (340 mg, 1.044 mmol). The mixture was heated to 80° C. and stirred overnight. The mixture was poured into water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure. The remaining material was dissolved in a minimal amount of dichloromethane and chromatographed on silica gel, eluting with a 5%-50% ethyl acetate in hexanes gradient to give the title compound (199 mg, 58%) as an oil that slowly solidified. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.41 (s, 9H), 3.91 (s, 3H), 3.94 (d, J=5 Hz, 2H), 4.38 (br s, 2H), 5.32-5.38 (m, 1H), 7.27 (d, J=1 Hz, 1H), 8.49 (d, J=1 Hz, 1H), 9.51 (s, 1H); LC-MS (LC-ES) M+H=365.

E. Methyl 4-(azetidin-3-yloxy)benzo[d]thiazole-6-carboxylate hydrochloride

To a stirred solution of methyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxylate (197 mg, 0.541 mmol) in methanol (2 mL) was added 4M hydrochloric acid in dioxane (2 mL, 8.00 mmol). The mixture was stirred for 2 hours during which time a yellow precipitate formed. Solvent was removed under reduced pressure and the remaining material was dried in vacuo to give the title compound (183 mg, 113%) as a yellow solid. This material was used without further purification. LC-MS (LC-ES) M+H=301.

F. Methyl 4-((1-(((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)carbamoyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxylate

To a stirred mixture of methyl 4-(azetidin-3-yloxy)benzo[d]thiazole-6-carboxylate hydrochloride (163 mg, 0.542 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.718 mmol), followed by 4-nitrophenyl ((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)carbamate (Intermediate 3) (200 mg, 0.620 mmol). The resulting yellow mixture was stirred overnight. The mixture was poured into 1N aqueous sodium hydroxide and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure. The remaining material was dissolved in a minimal amount of dichloromethane and chromatographed on silica gel, eluting with a 5%-80% ethyl acetate:ethanol (3:1 v/v) in hexanes gradient to give the title compound (151 mg, 62%) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1.02 (s, 6H), 1.06-1.15 (m, 5H), 1.79 (t, J=11 Hz, 4H), 3.25 (m, 1H), 3.86 (dd, J=9, 4 Hz, 2H), 3.91 (s, 3H), 4.00-4.07 (m, 1H), 4.31 (dd, J=9, 6 Hz, 2H), 5.30 (t, J=4 Hz, 1H), 6.23 (d, J=8 Hz, 1H), 7.26 (d, J=1 Hz, 1H), 8.48 (d, J=1 Hz, 1H), 9.51 (s, 1H); LC-MS (LC-ES) M+H=448.

G. 4-((1-(((trans)-4-(2-Hydroxypropan-2-yl)cyclohexyl)carbamoyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxylic acid

To a stirred mixture of methyl 4-((1-(((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)carbamoyl)azetidin-3-yl)oxy)benzo[d]thiazole-6-carboxylate (136 mg, 0.304 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added 1M aqueous lithium hydroxide (1 mL, 1.000 mmol). The mixture was stirred 1.5 hours and then evaporated under reduced pressure. The remaining material was diluted with water, poured into 1N aqueous hydrochloric acid and extracted with ethyl acetate. A white gelatinous suspension formed in the aqueous layer. The aqueous layer was separated and extraction with dichloromethane was attempted. The mixture remained a gelatinous suspension and was vacuum filtered. The collected solid was placed in vacuo to give the title compound (84 mg, 64%) as a white solid. The ethyl acetate layer from the initial extraction was washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure and the remaining solid was placed in vacuo to give additional title compound (30 mg, 23%) as a yellow solid. The two aqueous work up layers were combined and further extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure and the remaining solid was placed in vacuo to give additional title compound (17 mg, 13%) as a white solid. 1 H NMR (400 MHz, CD 3 SOCD 3 ) δ 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.02 (s, 6H), 1.06-1.18 (m, 5H), 1.74-1.84 (m, 4H), 3.29 (br s, 1H), 3.86 (dd, J=9, 3 Hz, 2H), 4.30 (dd, J=9, 6 Hz, 2H), 5.29 (br s, 1H), 6.22 (d, J=8 Hz, 1H), 7.25 (d, J=1 Hz, 1H), 8.43 (d, J=1 Hz, 1H), 9.49 (s, 1H); LC-MS (LC-ES) M+H=434.