WO2018007973A2

WO2018007973A2 - Process and intermediates for preparing benzoxazepines

Info

Publication number: WO2018007973A2
Application number: PCT/IB2017/054077
Authority: WO
Inventors: Jae U. Jeong; Jianxing Kang; Lara Kathryn LEISTER; Joseph J. Romano
Original assignee: GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2016-07-06
Filing date: 2017-07-06
Publication date: 2018-01-11
Anticipated expiration: 2019-01-06
Also published as: WO2018007973A3

Abstract

Disclosed is a new process and intermediates for preparing benzoxazepines of Formula (I): (I) wherein Q is, and A, L, B, RA and m are as defined herein.

Description

PROCESS AND INTERMEDIATES FOR PREPARING BENZOXAZEPINES

Field of the Invention

This invention relates to processes and intermediates for preparing benzoxazepine compounds that function as RIPl kinase inhibitors.

Background of the Invention

Dysregulation of RIPl kinase-mediated programmed cell death has been linked to various inflammatory diseases, as demonstrated by use of the RIP3 knockout mouse (where RIPl -mediated programmed necrosis is completely blocked) and by Necrostatin- 1 (a tool inhibitor of RIPl kinase activity with poor oral bioavailability). The RIP3 knockout mouse has been shown to be protective in inflammatory bowel disease (including Ulcerative colitis and Crohn's disease) ((2011) Nature 477, 330-334), Psoriasis ((2011) Immunity 35, 572-582), retinal-detachment-induced photoreceptor necrosis ((2010) PNAS 107, 21695-21700), retinitis pigmentosa ((2012) Proc. Natl.

Acad. Sci., 109:36, 14598-14603), cerulein-induced acute pancreatits ((2009) Cell 137, 1100-111 1) and Sepsis/systemic inflammatory response syndrome (SIRS) ((2011) Immunity 35, 908-918). Necrostatin-1 has been shown to be effective in alleviating ischemic brain injury ((2005) Nat. Chem. Biol. 1, 112-119), retinal ischemia/reperfusion injury ((2010) J. Neurosci. Res. 88, 1569-1576), Huntington's disease ((2011) Cell Death Dis. 2 el 15), renal ischemia reperfusion injury ((2012) Kidney Int. 81, 751-761), cisplatin induced kidney injury ((2012) Ren. Fail. 34, 373-377) and traumatic brain injury ((2012) Neurochem. Res. 37, 1849-1858). Other diseases or disorders regulated at least in part by RIPl -dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies ((2013) Genes Dev. 27: 1640-1649), bacterial infections and viral infections ((2014) Cell Host & Microbe 15, 23-35) (including, but not limited to, tuberculosis and influenza ((2013) Cell 153, 1-14)) and Lysosomal storage diseases (particularly, Gaucher Disease, Nature Medicine Advance Online Publication, 19 lanuary 2014, doi: 10.1038/nm.3449).

Potent and selective, small molecule inhibitors of RIPl kinase activity and methods of making and using the same are described in WO2014/125444 (International Patent Application No. PCT/IB2014/059004), the disclosure of which is incorporated herein intis entirety. An improved method of preparing these compounds would be desirable.

SUMMARY OF THE INVENTION

This invention is directed to a process for preparing a benzoxazepine of

Formul

ZUs CH or CR¹;

Z² is CH or CR²;

Z³ is CH or CR³;

Z⁴ is CH or CR⁴;

R¹ is fluoro or methyl;

one of R² and R³ is halogen, cyano, (Ci-Ce)alkyl, halo(Ci-C4)alkyl,

(Ci-C₆)alkoxy, halo(Ci-C₄)alkoxy, hydroxyl, B(OH)₂, -COOH,

halo(Ci-C4)alkylC(OH)₂-, (Ci-C4)alkoxy(Ci-C4)alkoxy, (Ci-C₄)alkylS02-,

(Ci-C4)alkylS0₂NHC(0)-, (Ci-C₄)alkylC(0)NH-, ((Ci-C4)alkyl)((Ci-C₄)alkyl)NC(0)- (Ci-C₄)alkylOC(0)-, (Ci-C4)alkylC(0)N(Ci-C₄)alkyl)-, (Ci-C₄)alkylNHC(0)-, (Ci-C4)alkoxy(C2-C4)alkylNHC(0)-, (Ci-C4)alkoxy(C2-C4)alkylC(0)NH-,

(Ci-C4)alkoxy(C2-C4)alkylNHC(0)NH-, (Ci-C4)alkylS02(C2-C4)alkylNHC(0)-, (Ci-C₄)alkylNHC(0)NH-, (Ci-C₄)alkylOC(0)NH-, hydroxy(Ci-C4)alkylOC(0)NH-, 5-6 membered heterocycloalkyl-C(O)-, 5-6 membered

heterocycloalkyl-(Ci-C4)alkyl-NHC(0)-, 5-6 membered

heterocycloalkyl-(Ci-C4)alkoxy-, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(0)NH, wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (Ci-C4)alkyl and -(Ci-C4)alkyl-CN;

and the other of R² and R³ is halogen, cyano or (Ci-Ce)alkyl;

R⁴ is romethyl;

Q is

A is phenyl, 5-6 membered heteroaryl, or 5-6 membered

heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on

ring A;

m is 0 or m is 1 and R^A is (Ci-C4)alkyl; and

L is O, S, NH, N(CH₃), CHi, CH2CH2, CH(CH₃), CHF, CF2, CH2O,

CH₂N(CH₃), CH2NH, or CH(OH); and

B is an optionally substituted (C3-C6)cycloalkyl, phenyl, 5-6

membered heteroaryl, or 5-6 membered heterocycloalkyl;

wherein said (C3-Ce)cycloalkyl, phenyl, 5-6 membered heteroaryl, or

5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or

two substituents each independently selected from halogen, (Ci-C4)alkyl,

halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, nitro, and

(Ci-C₄)alkylC(0)-;

or the moiety -L-B is (C3-C6)alkyl, (C3-C6)alkoxy, halo(C3-C6)alkoxy,

(C3-C6)alkenyl, or (C3-C6)alkenyloxy;

or a salt, particularly a pharmaceutically acceptable salt, thereof;

wherein the process comprises converting a substituted (¾i-3-hydroxy-N-methyl- 2-aminopropanamide having Formula (II):

wherein W is OH or fluoro and R^P is an amine protecting group, into a 2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one having Formula (IV):

or a salt, particularly a pharmaceutically acceptable salt, thereof.

This process further comprises converting the compound of Formula (IV), or a salt thereof, into the compound of Formula (I), or a salt thereof, which process comprises reacting the compound of Formula (IV), or a salt thereof, with an appropriate carboxylic acid or carboxylic acid derivative.

Other aspects of this invention include a compound which is:

(iS)-fert-butyl (3-hydroxy- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-2- yl)carbamate,

(<S)-benzyl (3-hydroxy- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-2- yl)carbamate,

(iS)-fert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)carbamate, (iS)-fert-butyl (3 -(Y-butoxy)- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-2- yl)carbamate,

(<S)-benzyl (5 -methyl-4-oxo-2,3 ,4,5 -tetrahydrobenzo [b] [1,4] oxazepin-3 -yl)carbamate, (5)-2-amino-3-hydroxy-N-(2-hydroxyphenyl)-N-methylpropanamide,

(5)-3-hydroxy-N-(2-hydroxyphenyl)-N-methyl-2-(tritylamino) propanamide,

(5)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)-one,

(5)-3-hydroxy-N-(2-hydroxyphenyl)-N-methyl-2-(tritylamino) propanamide,

(iS)-fert-butyl (3-(feri-butoxy)-l-((2-fluorophenyl)amino)- l-oxopropan-2-yl)carbamate, (S)-tert-butyl (3-(feri-butoxy)-l-((2-fluorophenyl)(methyl)amino)- l-oxopropan-2- yl)carbamate,

(5)-2-amino-N-(2-fluorophenyl)-3-hydroxy-N-methylpropanamide,

(5)-N-(2-fluorophenyl)-3-hydroxy-N-methyl-2-(tritylamino)propanamide,

(5)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)-one,

(5)-3-amino-5-methyl-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)-one,

or a salt thereof, and the process for the preparation thereof. DETAILED DESCRIPTION OF THE INVENTION

This invention is further directed to a process for preparing a benzoxazepine of Formula (I), wherein:

Z^s CH or CR¹;

Z² is CH or CR²;

Z³ is CH or CR³;

Z⁴ is CH or CR⁴;

R¹ is fluoro or methyl;

one of R² and R³ is halogen, cyano, (Ci-Ce)alkyl, halo(Ci-C₄)alkyl,

(Ci-C₆)alkoxy, halo(Ci-C₄)alkoxy, hydroxyl, B(OH)₂, -COOH,

halo(Ci-C4)alkylC(OH)₂-, (Ci-C4)alkoxy(Ci-C4)alkoxy, (Ci-C )alkylS0₂-,

(Ci-C4)alkylS0₂NHC(0)-, (Ci-C )alkylC(0)NH-, ((Ci-C )alkyl)((Ci-C )alkyl)NC(0)-, (Ci-C )alkylOC(0)-, (Ci-C₄)alkylC(0)N(Ci-C )alkyl)-, (Ci-C )alkylNHC(0)-, (Ci-C )alkoxy(C₂-C )alkylNHC(0)-, (Ci-C )alkoxy(C₂-C )alkylC(0)NH-,

(Ci-C )alkoxy(C₂-C )alkylNHC(0)NH-, (Ci-C )alkylS0₂(C₂-C )alkylNHC(0)-,

(Ci-C )alkylNHC(0)NH-, (Ci-C )alkylOC(0)NH-, hydroxy(Ci-C )alkylOC(0)NH-, 5-6 membered heterocycloalkyl-C(O)-, 5-6 membered

heterocycloalkyl-(Ci-C₄)alkyl-NHC(0)-, 5-6 membered

heterocycloalkyl-(Ci-C₄)alkoxy-, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(0)NH,

wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (Ci-C₄)alkyl and -(Ci-C₄)alkyl-CN;

and the other of R² and R³ is halogen or (Ci-Ce)alkyl;

R⁴ is fluoro, chloro, or methyl;

A is phenyl, 5-6 membered heteroaryl, or 5-6 membered

heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on

ring A;

m is 0 or m is 1 and R^A is (Ci-C₄)alkyl; and

L is O, S, NH, N(CH₃), CH₂, CH₂CH₂, CH(CH₃), CHF, CF₂, CH₂0,

CH₂N(CH₃), CH₂NH, or CH(OH); and

B is an optionally substituted (C3-C6)cycloalkyl, phenyl, 5-6

membered heteroaryl, or 5-6 membered heterocycloalkyl; wherein said (C3-C6)cycloalkyl, phenyl, 5-6 membered heteroaryl, or

5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or

two substituents each independently selected from halogen, (Ci-C4)alkyl,

halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, nitro, and

(Ci-C₄)alkylC(0)-;

or the moiety -L-B is (C3-Ce)alkyl, (C3-Ce)alkoxy, halo(C3-Ce)alkoxy,

(C3-C6)alkenyl, or (C3-Ce)alkenyloxy;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms. The term

"(Ci-C4)alkyl" refers to an alkyl moiety containing from 1 to 4 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, ^-propyl, isopropyl, «-butyl, isobutyl, s -butyl, and /-butyl.

When a substituent term such as "alkyl" is used in combination with another substituent term, for example as in "hydroxy(Ci-C4)alkyl" or "aryl(Ci-C4)alkyl", the linking substituent term (e.g., alkyl) is intended to encompass a divalent moiety, wherein the point of attachment is through that linking substituent. Examples of "aryl(Ci- C4)alkyl" groups include, but are not limited to, benzyl (phenylmethyl), 1-methylbenzyl (1-phenylethyl), and phenethyl (2-phenylethyl). Examples of "hydroxy(Ci-C4)alkyl" groups include, but are not limited to, hydroxymethyl, hydroxyethyl, and

hydroxyisopropyl.

The term "halo(Ci-C4)alkyl" represents a group having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms. Examples of "halo(Ci-C4)alkyl" groups include, but are not limited to, -CF3 (trifluoromethyl), -CCI3 (trichloromethyl), 1, 1- difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

"Alkoxy" refers to an "alkyl-oxy-" group, containing an alkyl moiety attached through an oxygen linking atom. For example, the term "(Ci-C4)alkoxy" represents a saturated, straight or branched hydrocarbon moiety having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(Ci-C4)alkoxy" groups include, but are not limited to, methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, s- butoxy, and 7-butoxy. The term "halo(Ci-C4)alkoxy" refers to a "haloalkyl-oxy-" group, containing a "halo(Ci-C4)alkyl" moiety attached through an oxygen linking atom, which

halo(Ci-C4)alkyl" refers to a moiety having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms. Exemplary "halo(Ci-C4)alkoxy" groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), -OCH2CF3 (trifluoroethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).

A carbocyclic group is a cyclic group in which all of the ring members are carbon atoms, which may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic). The term "carbocyclic" includes cycloalkyl and aryl groups.

"Cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term

"(C3-C6)cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to six ring carbon atoms. Exemplary "(C3-C6)cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The terms "cycloalkyloxy" or "cycloalkoxy" refer to a group containing a cycloalkyl moiety, defined hereinabove, attached through an oxygen linking atom. Exemplary "(C3-C6)cycloalkyloxy" groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

"Aryl" refers to a group or moiety comprising an aromatic, monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" groups are phenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Generally, in the compounds of Formula (I), aryl is phenyl.

A heterocyclic group is a cyclic group having, as ring members, atoms of at least two different elements, which cyclic group may be saturated (non-aromatic) or fully unsaturated (aromatic). The terms "heterocyclic" or "heterocyclyl" includes heterocycloalkyl and heteroaryl groups.

"Heterocycloalkyl" refers to a non-aromatic, monocyclic or bicyclic group containing 3-10 ring atoms, being fully saturated and containing one or more (generally one or two) heteroatom substitutions independently selected from oxygen, sulfur, and nitrogen. Examples of "heterocycloalkyl" groups include, but are not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,

tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl.

Examples of "4-membered heterocycloalkyl" groups include oxetanyl, thietanyl and azetidinyl.

The term "5-6-membered heterocycloalkyl" represents a non aromatic, monocyclic group, which is fully saturated, containing 5 or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 5 to 6-membered heterocycloalkyl groups include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and thiomorpholinyl.

"Heteroaryl" represents a group or moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic -aryl groups containing either an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety.

Illustrative examples of heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl (pyridyl), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl,

dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6- naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.

As used herein, "5-6-membered heteroaryl" represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 5- membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of 5- membered heteroaryl groups include furyl (furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl. Selected 6-membered heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

Bicyclic heteroaryl groups include 6,5 -fused heteroaryl (9-membered heteroaryl) and 6,6-fused heteroaryl (10-membered heteroaryl) groups. Examples of 6,5-fused heteroaryl (9-membered heteroaryl) groups include benzothienyl, benzoiuranyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, indolizinyl, isobenzofuryl,

2,3-dihydrobenzofuryl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl, l,3-benzoxathiol-2-on-yl (2-oxo-l,3-benzoxathiolyl), purinyl and imidazopyridinyl.

Examples of 6,6-fused heteroaryl (10-membered heteroaryl) groups include quinolyl, isoquinolyl, phthalazinyl, naphthridinyl (1,5-naphthyridinyl, 1,6- naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl), quinazolinyl, quinoxalinyl, 4H-quinolizinyl, tetrahydroquinolinyl, cinnolinyl, and pteridinyl.

Unless otherwise specified, all bicyclic ring systems may be attached at any suitable position on either ring.

The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents. "Oxo" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = O). "Hydroxy" or "hydroxyl" is intended to mean the radical -OH. As used herein, the term "cyano" refers to the group - CN.

As used herein, the term "optionally substituted" indicates that a group (such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group) or ring or moiety (such as a carbocyclic or heterocyclic ring or moiety) may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent(s) as defined. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

In one embodiment of the compounds of Formula (I) prepared by the process of this invention, Z¹, Z², Z³, and Z⁴ are each CH. In another

embodiment, Z¹ is CR¹ and Z², Z³ and Z⁴ are each CH. In a further embodiment, Z¹, Z², and Z⁴ are each CH and Z³ is CR³. In a further embodiment, Z¹, Z³, and Z⁴ are each CH and Z² is CR². In a still further

embodiment, Z¹, Z², and Z³ are each CH and Z⁴ is CR⁴. In another

embodiment, Z¹ and Z² are CH, Z³ is CR³, and Z⁴ is CR⁴. In another

embodiment, Z¹ and Z⁴ are CH, Z² is CR², and Z³ is CR³. In another

embodiment, Z¹ and Z³ are CH, Z² is CR², and Z⁴ is CR⁴. In another

embodiment, Z¹ is CH, Z² is CR², Z³ is CR³, and Z⁴ is CR⁴.

In one embodiment of the compounds of Formula (I) prepared by the process of this invention, R¹ is fluoro. In another embodiment, R¹ is methyl.

In one embodiment of the compounds of Formula (I) prepared by the process of this invention, one of R² and R³ is halogen, cyano, (Ci-Ce)alkyl, halo(Ci-C4)alkyl, (Ci-C₆)alkoxy, halo(Ci-C₄)alkoxy, hydroxyl, B(OH)₂, -COOH,

halo(Ci-C4)alkylC(OH)₂-, (Ci-C4)alkoxy(Ci-C4)alkoxy, (Ci-C₄)alkylS02-,

(Ci-C4)alkylS0₂NHC(0)-, (Ci-C₄)alkylC(0)NH-, ((Ci-C4)alkyl)((Ci-C₄)alkyl)NC(0)-, (Ci-C₄)alkylOC(0)-, (Ci-C4)alkylC(0)N(Ci-C₄)alkyl)-, (Ci-C₄)alkylNHC(0)-, (Ci-C4)alkoxy(C₂-C4)alkylNHC(0)-, (Ci-C4)alkoxy(C₂-C4)alkylC(0)NH-,

(Ci-C4)alkoxy(C₂-C4)alkylNHC(0)NH-, (Ci-C4)alkylS0₂(C₂-C₄)alkylNHC(0)-, (Ci-C4)alkylNHC(0)NH-, (Ci-C4)alkylOC(0)NH-, hydroxy(Ci-C4)alkylOC(0)NH-, 5-6 membered heterocycloalkyl-C(O)-, 5-6 membered

heterocycloalkyl-(Ci-C4)alkyl-NHC(0)-, 5-6 membered

heterocycloalkyl-(Ci-C4)alkoxy-, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(0)NH,

wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (Ci-C4)alkyl and -(Ci-C4)alkyl-CN;

and the other of R² and R³ is halogen, cyano or (Ci-Ce)alkyl.

In another embodiment, R² is halogen, cyano, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-C₄)alkoxy, hydroxyl, B(OH)₂, -COOH, halo(Ci-C₄)alkylC(OH)₂-,

(Ci-C4)alkoxy(Ci-C4)alkoxy, 3-5 membered cycloalkyl, or 5-6 membered heteroaryl, wherein said 3-5 membered cycloalkyl or 5-6 membered heteroaryl is optionally substituted by a (Ci-C3)alkyl substituent; and Z³ is CH or CR³ and R³ is cyano, (Ci-Ce)alkyl, or a 5-6 membered heteroaryl, optionally substituted by a (Ci-C3)alkyl substituent. In another embodiment, R² is halogen, cyano, (Ci-Ce)alkyl, hydroxyl, B(OH)₂, -COOH, halo(Ci-C4)alkylC(OH)₂-, (Ci-C4)alkoxy(Ci-C4)alkoxy, or 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by a (Ci-C3)alkyl substituent; and Z³ is CH.

In another embodiment, R³ is halogen, (Ci-Ce)alkyl, halo(Ci-C4)alkyl, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, B(OH)₂, -COOH, (Ci-C₄)alkylS02-,

(Ci-C4)alkylS0₂NHC(0)-, (Ci-C₄)alkylC(0)NH-, ((Ci-C4)alkyl)((Ci-C₄)alkyl)NC(0)-, (Ci-C₄)alkylOC(0)-, (Ci-C4)alkylC(0)N(Ci-C₄)alkyl)-,

heterocycloalkyl-(Ci-C4)alkyl-NHC(0)-, 5-6 membered

heterocycloalkyl-(Ci-C4)alkoxy-, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(0)NH, herein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by (Ci-C3)alkyl or -(Ci-C3)alkyl-CN; and Z² is CH.

In specific embodiments of the compounds of Formula (I) prepared by the process of this invention, R² is fluoro, chloro, bromo, -CN, -CH3,

-OCH3, -OCHF₂, -OH, B(OH)₂, CF₃C(OH)₂-, CH₃OCH₂CH₂0-,

cyclopropyl, 5H-tetrazol-5-yl, pyrazol-3-yl, or 5-methyl-l,3,4-oxadiazol-2- yi.

In specific embodiments of the compounds of Formula (I) prepared by the process of this invention, R³ is fluoro, chloro, bromo, -CN, -OCH3,

-OCHF₂, B(OH)₂, -COOH, CH₃S0₂-, CH₃S0₂NHC(0)-, CH₃C(0)NH-,

(CH₃)₂NC(0)-, CH₃OC(0)-, (CH₃)C(0)N(CH₃)-, HOCH₂CH₂C(0)NH-,

CH₃OCH₂CH₂NHC(0)NH-, CH₃S0₂CH₂CH₂NHC(0)-,

CH₃CH₂NHC(0)NH-, CH₃OC(0)NH-, morpholin-4-yl-CO-, pyrrolidin-1- yl-CH₂CH₂NHC(0)-, pyridin-2-yl, tetrahydrofuran-2-yl-CH₂0-,

pyrrolidin- 1 -yl-CH₂CH₂0-, tetrazol-5-yl, 1 -(2-cyanoethyl)-tetrazol-5-yl,

pyrazol-l-yl, pyrazol-3-yl, pyrazol-4-yl, l-methyl-pyrazol-3-yl, 1-methyl- pyrrol-4-yl-C(0)NH-, 5-methyl-l,3,4-oxadiazol-2-yl, or 5-oxo-4,5-dihydro- l,3,4-oxadiazol-2-yl.

In one embodiment of the compounds of Formula (I) prepared by the process of this invention, R⁴ is fluoro, chloro, methyl, or trifluoromethyl. In

another embodiment, R⁴ is fluoro. In yet another embodiment, R⁴ is methyl. In a specific embodiment, this invention is directed to a process for

preparing a compound of Formula (I) wherein Z¹, Z², Z³, and Z⁴ are each CH;

or Z¹, Z², and Z⁴ are each CH and Z³ is CR³; or Z¹, Z³, and Z⁴ are each CH

and Z² is CR²; or Z¹, Z², and Z³ are each CH and Z⁴ is CR⁴; or Z¹ and Z³ are

CH, Z² is CR², and Z⁴ is CR⁴; R² is fluoro, chloro, bromo, or -CH3; R³ is 5- methyl-l,3,4-oxadiazol-2-yl; R⁴ is fluoro; A is triazolyl; m is 0; L is CH2;

and B is cyclopentyl or phenyl; or a salt, particularly a pharmaceutically

acceptable salt thereof.

In another specific embodiment, this invention is directed to a process for preparing a compound of Formula (I) wherein Z¹, Z², Z³, and Z⁴ are each

CH; or Z¹ and Z³ are CH, Z² is CR², and Z⁴ is CR⁴; R² is fluoro; R⁴ is fluoro;

A is triazolyl; m is 0; L is CH2; and B is phenyl; or a salt, particularly a

pharmaceutically acceptable salt thereof.

Previously, benzoxazepine compounds of Formula (IV) have been prepared by cyclization of an ortho-substituted (hetero)aryl amine using a conventional amide coupling agent (e.g., HATU (0-(7-Azabenzotriazol-lyl)-N,N,N',N'-tetramethylyronium hexafluorophosphate) in the presence of a base, diisopropyl ethylamine (DIEA or DIPEA)), followed by alkylation (e.g., methyl iodide, in the presence of a mild base, potassium carbonate) as follows, where the nitrogen protecting group R^PA may be the same or different from the R^p protecting group used in the present invention:

Starting substituted aniline (aryl amine) compounds can be prepared by reduction of the corresponding ortho-substituted nitro-compound or may be prepared by condensation of N-protected (R^PA) -L-serine with an appropriately substituted aniline compound in the presence of a base.

The use of aromatic nitro and/or aromatic amine compounds in the synthesis of materials intended for human consumption may be problematic, as such nitro and/or amine compounds may be highly toxic or reactive. Accordingly, it was desirable to develop a safe, scalable, and efficient new method for preparation of the benzoxazepine compounds of Formula (I).

The present invention provides a method for the preparation of the compounds of Formula (I), or a salt thereof, wherein the process comprises converting a substituted (S)- 3-hydroxy-N-methyl-2-

or a salt thereof.

When W is OH, the cyclization process proceeds via a Mitsunobu-type cyclization and may be conducted under conventional conditions using

triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD). 1,1'- (Azodicarbonyl)dipiperidine (ADDP) or diisopropyl azodicarboxylate (DIAD) may be used instead of DEAD. A polymer-supported triphenylphosphine (PS-PPI13) may be used instead of TPP.

When W is fluoro, the cyclization process proceeds as a nucleophilic aromatic substitution reaction (SNAr) which is typically conducted in the presence of a base, for example cesium carbonate. Other bases that may be useful in this reaction include sodium hydride, sodium carbonate or potassium carbonate. More specifically, the present invention provides a method for the preparation of the compounds of Formula (I), or a salt thereof, wherein the process comprises:

1) cyclizing a substituted (¾i-3-hydroxy-N-methyl-2-aminopropanamide having Formula (II):

wherein W is OH or fluoro and R^p is an amine protecting group, to form a 2,3- dihydrobenzo[b][l,4]o la (III):

(III); and

2) converting the compound of Formula (III) into the compound of Formula (IV):

In this process, R^p is an amine protecting group that is stable to the reaction conditions under which the cyclization reaction is conducted. Suitable protecting groups for amines and the methods for protecting and deprotecting such substituents are well known to those skilled in the art; examples of which may be found in P.G.M. Wuts and T.W. Greene, Greene 's Protective Groups in Chemical Synthesis (4th ed.), John Wiley & Sons, NJ (2007).

In the examples provided herein, the nitrogen protecting group (R^p) is a triphenylmethyl (trityl) group. Other nitrogen protecting groups that may be useful in this reaction include a fert-butyloxycarbonyl (Boc) group.

Methods for removal of nitrogen protecting groups are well known in the art. For example, trityl and Boc nitrogen protecting groups are typically removed by acid treatment, such as by trifluoroacetic acid or hydrochloric acid, in a suitable solvent, such as methanol, methylene chloride, or dioxane, or mixtures thereof. A benzyloxycarbonyl (Cbz ) group is generally removed by hydrogenation over a palladium catalyst.

As provided herein, a process for removal of a trityl nitrogen protecting group in the compound of Formula (III) comprises treatment of the compound of Formula (III) with hydrochloric acid in dioxane, methanol and/or methylene chloride to form the amine compound of Formula (IV).

A compound of Formula (I) may be formed by a process comprising reacting the compound of Formula (IV) with a carboxyl -containing compound of Formula (V).

(IV) (V) (I)

This reaction may be accomplished using conventional amide-forming reaction conditions. (See, for example, S.-Y. Han and Y.-A. Kim, Tetrahedron 60 (2004) 2447- 2467 and ChemFiles Vol. 7, No. 2, (2007) 1-19). As provided herein, a process for forming the exo-cyclic amide bond in a compound of Formula (I) comprises reacting the compound of Formula (IV) with a compound of Formula (V) in the presence of DIEA and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (propylphosphonic anhydride,T3P).

The starting substituted aniline compounds used in the process of this invention for preparing the compounds of Formula (I) are commercially available or can be prepared by routine methods well known in the art. Alternatively, the compounds of Formula (I) may be prepared from compounds of Formula (III) or Formula (IV), or other compounds of Formula (I) using methods well known in the art (hydrolysis, methylation/de-methylation, substitution or condensation reactions, etc.).

The process of this invention further comprises a process of making a compound of Formula (II). When W is OH, this process comprises converting an aniline compound of Formula (II-A):

into an amide compound of Formula (II-C):

by treating the compound of Formula (Π-Α) with a compound of Formula (II -B):

In this process, R^PA is a protecting group for an amino moiety, specifically a primary amine protecting group and R^x is H or R^PH, wherein R^PH is a protecting group for an alcohol moiety, that is, R^PH is a hydroxyl protecting group. The R^PA and R^PH protecting groups are suitably selected to be stable to the reaction conditions under which the amide-forming reaction is conducted. Suitable protecting groups for amine and hydroxyl substituents and the methods for protecting and deprotecting such substituents are well known to those skilled in the art; examples of which may be found in P.G.M. Wuts and T.W. Greene, Greene 's Protective Groups in Chemical Synthesis (4th ed.), John Wiley & Sons, NJ (2007) .

Suitable R^PA amine protecting groups that may be used include amides (including sulfonamides), carbamates (e.g., a fert-butyloxycarbonyl (Boc) group or

benzyloxycarbonyl (Cbz) group), and alkyl groups (e.g., a triphenylmethyl (trityl) group). As exemplified herein, R^PA can be a Boc group or a Cbz group.

Suitable R^PH hydroxyl protecting groups that may be used include acetals, ethers

(e.g., fert-butyl or trityl group, and including silyl ethers, e.g., frz-ethylsilyl, tert- butyldimethylsilyl, etc.), esters, carbonates, and carbamates (e.g., a Cbz group). As exemplified herein, R^PH can be a fert-butyl group.

This reaction may be accomplished using conventional amide-forming reaction conditions, as described above. As provided herein, a process for forming the amide bond in a compound of Formula (II-C) comprises reacting the compound of Formula (II- A) with a compound of Formula (II-B) using, as a coupling agent, T3P, in the presence of a non-nucleophilic base, for example, DIEA, in a suitable solvent, for example, isopropanol.

The process of this invention further comprises a process of converting the amide compound of Formula (II-C):

into an amino-amide compound of Formula (II-D):

This reaction may be accomplished in one or two steps using conventional techniques for de-protection of the amine and hydroxyl substituents, that is, removal of the nitrogen and hydroxyl protecting groups, as described and referenced herein.

Methods for removal of these protecting groups are well known in the art. Preferably, the R^PA and R^PH protecting groups are selected such that both groups can be removed in one step. More preferably, the R^PA and R^PH protecting groups are selected such that both groups can be removed using the same reaction conditions. Advantageously, when R^PA is a Boc (fert-butoxycarbonyl) group and R^PH is a fert-butyl group, both protecting groups can be removed in one step using acid hydrolysis.

As provided herein, a process for de-protecting the amino group and the hydroxyl group comprises reacting the compound of Formula (II-C) with an acid, for example hydrochloric acid in a suitable solvent, for example, dioxane. Under such conditions, the product may be isolated as the salt of the acid used. As described, herein, the compound of Formula (II-D) maybe isolated as a hydrochloride salt. The process of this invention further comprises a process of re-protecting the moiety of the compound of Formula (II-D) comprising converting the compound of Formula (II-D):

into the compound of Fo

wherein the compound of Formula (Π-Ε) corresponds to the compound of Formula (II), wherein W is OH. In this process, R^p is an amine protecting group that is stable to the reaction conditions under which the cyclization reaction is conducted. This reaction may be accomplished using conventional techniques for protection of the amine. Methods for the introduction of an amine protecting group are well known in the art, and are described and referenced above.

As provided herein, R^p may be a trityl group. The exemplified process for adding a trityl group as an amine protecting group to a compound of Formula (II-D) comprises treating a compound of Formula (II-D) with trityl chloride in the presence of a non- nucleophilic base, for example triethyl amine (TEA), in a suitable aprotic solvent, for example, chloroform.

The process of this invention further comprises a process of making a compound of Formula (II), wherein W is F. This aspect of the invention comprises converting an aniline of Formula (Π-Κ):

into an amide compound of Formula (II-L):

by treating the compound of Formula (II-K) with a compound of Formula (II -B):

As in the process described above, R^PA is an amine protecting group and R^x is H or R^PH, wherein R^PH is a hydroxyl protecting group. The R^PA and R^PH protecting groups are suitably selected to be stable to the reaction conditions under which the amide- forming reaction is conducted. As exemplified herein, R^PA of Formula (II-L) and (II-B) is a Boc group and R^PH is a fert-butyl group. Other suitable R^PA amine protecting groups and R^PH hydroxyl protecting groups are described hereinabove.

This reaction may be accomplished using conventional amide-forming reaction conditions. As provided herein, a process for forming the amide bond in a compound of Formula (II-L) comprises reacting the compound of Formula (II-K) with a compound of Formula (II-B), using as a coupling agent, T3P, in the presence of a non-nucleophilic base, for example, DIEA, in a suitable solvent, for example, methylene chloride.

The process of this invention further comprises a process of alkylating the amide-nitrogen in the compound of Formula (II-L), comprising converting the compound of Formula (II-L):

into an alkylated compound of Formula (II -M):

This reaction may be accomplished using conventional techniques for alkylation of an amine. As provided herein, this aspect of the process reacting the compound of Formula (II-L) with an alkylating agent, for example, methyl iodide, in the presence of a non-nucleophilic base, for example cesium carbonate, in a suitable aprotic solvent, for example, dimethyl formamide (DMF).

The process of this invention further comprises a process of converting the amide compound of Formula (II-M):

into an amino-amide compound of Formula (II-N):

Methods for removal of these protecting groups are well known in the art. Preferably, the Pv^PA and R^PH protecting groups are selected such that both groups can be removed in one step. More preferably, the R^PA and R^PH protecting groups are selected such that both groups can be removed using the same reaction conditions. Advantageously, when R^PA is a Boc (fert-butoxycarbonyl) group and R^PH is a fert-butyl group, both protecting groups can be removed in one step using acid hydrolysis.

As provided herein, a process for de-protecting the amino group and the hydroxyl group comprises reacting the compound of Formula (II-M) with an acid, for example hydrochloric acid in a suitable protic or aprotic solvent, for example, dioxane. Under such conditions, the product may be isolated as the salt of the acid used. As described, herein, the compound of Formula (II-N) maybe isolated as a hydrochloride salt.

The process of this invention further comprises a process of re-protecting the amino moiety of the compound of Formula (II-N) comprising converting the compound of Formula (II-N):

into the compound of Fo

where the compound of Formula (Π-0) corresponds to the compound of Formula (II), wherein W is F. In this process, R^p is an amine protecting group that is stable to the reaction conditions under which the cyclization reaction is conducted. This reaction may be accomplished using conventional techniques for protection of the amine. Methods for the introduction of an amine protecting group are well known in the art, and are described above. As provided herein, R^p may be a trityl group. The exemplified process for adding a trityl group as an amine protecting group to a compound of Formula (II-N) comprises treating a compound of Formula (II-N) with trityl chloride in the presence of a non-nucleophilic base, for example triethyl amine (TEA), in a suitable aprotic solvent, for example, carbon tetrachloride. The process of this invention further comprises a process of making a compound of Formula (II), wherein W is F. This aspect of the invention comprises converting an aniline of Formula (II-KM):

into an amide compound of Formula (II -M):

by treating the compound of Formula (II-KM) with a compound of Formula (II-B):

wherein R^PA and R^x are as described hereinabove and the reaction may be accomplished using the amide-forming reaction conditions described hereinabove. The subsequent conversion of the compound of Formula (II-M) to the compound of Formula (II-O) can be accomplished as described hereinabove.

One embodiment of this invention relates to a process for the preparation of a compound of Formula (IV-H

comprising the steps of:

1) treating a compound having Formula (II -AH):

with a compound having Formula (Π-Β):

wherein R^PA is an amine protecting group and R^x is H or R^PH, wherein R^PH is a hydroxyl protecting group, to form a compound of Formula (II-CH):

2) converting the compound of Formula (II-CH) into a compound of Formula (II- DH);

3) converting the compound of Formula (II-DH) into a compound of Formula (II- EH):

wherein R^p is an amine protecting group;

cyclizing the compound of Formula (II-EH) to form the compound of Formula

(III-H):

converting the compound of Formula (III-H) into the compound of Formula (IV-

H).

In one embodiment of the process of this invention, R^x is H. In another embodiment of the process of this invention, R^PA is a Boc group. In yet another embodiment, R^x is R^PH and R^PH is a fert-butyl group. In a further embodiment, R^p is a trityl group.

Another embodiment of this invention relates to a process for the preparation of compound of Formula (IV-

comprising the steps of:

1) treating a compound having Formula (II -KH):

with a compound having Formula (Π-Β):

wherein R^PA is an amine protecting group and R^x is H or R^PH, wherein R^PH is a hydroxyl protecting group, to form a compound of Formula (II-LH):

2) converting the compound of Formula (II-LH) into a compound of Formula (II- MH);

OR^x

' xNHR^PA

(II-MH),

3) converting the compound of Formula (II-MH) into a compound of Formula (II- NH):

4) converting the compound of Formula (II-NH) into a compound of Formula (II- OH):

wherein R^p is an amine protecting group, and cyclizing the compound of Formula (II-OH) to form the compound of Formula

(III-H):

converting the compound of Formula (III-H) into the compound of Formula (IV-

H).

comprising the steps of:

1) treating a compound having Formula (II -KM):

with a compound having Formula (Π-Β):

wherein R^PA is an amine protecting group and R^x is H or R^PH, wherein R^PH is a hydroxyl protecting group, to form a compound of Formula (II-MH);

converting the compound of Formula (II-MH) into a compound of Formula (II

4) converting the compound of Formula (II-NH) into a compound of Formula (II OH):

wherein R^p is an amine protecting group, and

cyclizing the compound of Formula (II-OH) to form the compound of Formula

6) converting the compound of Formula (III-H) into the compound of Formula (IV- In this embodiment of the process of this invention, R^x, R^PA, and R^p are as defined herein.

A specific embodiment of this invention relates to a process for the preparation of a compound of Formula I, having the formula:

comprising the steps of:

1) treating 2-(methylamino)phenol hydrochloride with (S)-3-(fert-butoxy)-2-((fert- butoxycarbonyl)amino)propanoic acid having the formula:

to form a compound h

converting the compound formed in step 1) to a compound having the formula:

3) converting the compound formed in step 2) to a compound having the formula:

converting the compoun mpound having the formula:

6) treating the compound formed in step 5) with a compound having the formula:

to form the compound of Formula I.

Another specific embodiment of this invention relates to a process for the preparation of a compound of Formula I, having the formula:

comprising the steps of:

1) treating 2-fluoroaniline with (S)-3-(fert-butoxy)-2-((fert- butoxycarbonyl)amino)propanoic acid having the formula:

a compound having the formula:

converting the compound formed in step 1) to a compound having the formula:

converting the compound formed in step 2) to a compound having the formula:

converting the compound formed in step 3) to a compound having the formula:

converting the compound formed in step 4) to a compound having the formula:

converting the compoun mpound having the formula:

treating the compound form with a compound having the formula:

to form the compound of Formula (I).

comprising the steps of:

1) treating 2-fluoroN-methylaniline with (S)-3-(fert-butoxy)-2-((fert- butoxycarbonyl)amino)propanoic acid having the formula:

a compound having the formula:

converting the compound formed in step 1) to a compound having the formula:

converting the compound compound having the formula:

converting the compoun mpound having the formula:

treating the compound form with a compound having the formula:

to form the compound of Formula (I).

It will be understood that a compound of any one of Formulas (I)-(V), (II-A)-(II- D) and (II-K)/(II-KM)-(II-0) may be present and/or used in the process of this invention in a salt or non-salt form. Because of their potential use in medicine, the salts of the compounds of Formulas (I)-(V), (II-A)-(II-D) and (II-K)-(II-O), are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts.

As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of the compounds of Formula (I) which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula (I) and their salts and solvates.

Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I), particularly a compound of any one of Formulas (I-IV). If a basic compound of Formula (I-IV) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK_a than the free base form of the compound. Similarly, if a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK_a than the free acid form of the compound. This invention also provides for the conversion of one salt of a compound of this invention, e.g., a hydrochloride salt, into another salt of a compound of this invention, e.g., a sulfate salt.

Salts of the compounds of Formula (I), particularly compounds of Formulas (I -IV), containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, such as treatment of the free base with an acid.

Examples of pharmaceutically acceptable salts so formed include acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, camphorate, camphor-sulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), carbonate, bicarbonate, cinnamate, citrate, cyclamate, dodecylsulfate (estolate), ethane- 1,2- disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate

(mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hippurate,

hydrobromide, hydrochloride, hydroiodide, isobutyrate, lactate, lactobionate, laurate, maleate, malate, malonate, mandelate, methanesulfonate (mesylate), naphthalene- 1,5- disulfonate (napadisylate), naphthalene-sulfonate (napsylate), nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, phosphate, diphosphate, proprionate, pyroglutamate, salicylate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, /j>-toluenesulfonate (tosylate), undecylenate, l-hydroxy-2-naphthoate, 2,2-dichloroacetate, 2- hydroxy ethane sulfonate (isethionate), 2-oxoglutarate, 4-acetamidobenzoate, and 4- aminosalicylate.

Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a

pharmaceutically acceptable salt may be made with a base which affords a

pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N-dibenzylethylenediamine, 2- hydroxyethylamine, 6zs-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N-bisdehydroabietylamine, glucamine, N- methylglucamine, collidine, choline, quinine, quinoline, and basic amino acids such as lysine and arginine. In one embodiment, the pharmaceutically acceptable base-addition salt of a compound of Formula (I) is a sodium salt or a potassium salt thereof. Because the compounds of Formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

EXAMPLES

The following examples illustrate the invention. Names for the intermediate and final compounds described herein were generated using the software naming program ACD/Name Pro V6.02 available from Advanced Chemistry Development, Inc., 1 10 Yonge Street, 14^th Floor, Toronto, Ontario, Canada, M5C 1T4

(http : //www . acdlab s . com/) or the naming program in ChemDraw, Struct=Name Pro 12.0, as part of ChemBioDraw Ultra, available from CambridgeSoft. 100

CambridgePark Drive, Cambridge, MA 02140 USA (www.cambridgesoft.com).

It will be appreciated by those skilled in the art that in certain instances these programs may name a structurally depicted compound as a tautomer of that compound. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof.

Abbreviations and symbols commonly used in the chemical arts are used herein to describe the compounds, reactions and reagents of this invention. In the following experimental descriptions, the following abbreviations may be used:

Preparation 1

Ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate

To a solution of 2-phenylacetohydrazide (20 g, 133 mmol) in ethanol (75 inL) and Et20 (250 mL) was added ethyl 2-ethoxy-2-iminoacetate (20 g, 138 mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. A precipitate started to form after 10 minutes. The resulting solid was filtered off, rinsed with Et20 and dried to give ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate (27.85 g, yield 82%) as a white solid, which was used without further purification. MS (m/z) 250

(M+H⁺).

Preparation 2

Ethyl 2-amino-2-(2-(2-(3-fluorophenyl)acetyl)hydrazono)acetate

2-(3-Fluorophenyl)acetohydrazide (2.90 g, 17.22 mmol) and ethyl 2-ethoxy-2- iminoacetate (2.5 g, 17.22 mmol) in ethanol (30 mL) was stirred under nitrogen at rt overnight. The resultant suspension was filtered. The white solid was washed with EtOH and dried under vacuum to give the title compound ethyl 2-amino-2-(2-(2-(3- fluorophenyl)acetyl)hydrazono)acetate (3 g, 11.23 mmol, 65.2 % yield), which was used without further purification. MS (m/z) 268 (M+H⁺).

The following intermediates used for the preparation of titled example

Preparation 3

Ethyl 5 -benzyl-4H- 1 ,2,4-triazole-3 -carboxylate

Ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate (27.85 g, 109 mmol) was suspended in xylenes (300 mL) and heated at 170 °C for 24 hours with a Dean-Stark trap. Initially a very thick mixture formed which became light yellow and homogeneous as the reaction progressed. The reaction was cooled to room temperature and a solid precipitated out. Diethyl ether was added and the reaction mixture stirred for 15 minutes in an ice/water bath. The solid was filtered off, rinsing with Et20 and hexanes, and dried to give ethyl 5 -benzyl-4H-l,2,4-triazole-3 -carboxylate (24.67 g, 95% yield) as a white solid, which was used without further purification. MS (m/z) 232 (M+H⁺). Preparation 4

Ethyl 5-(3-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate

Ethyl 2-amino-2-(2-(2-(3-fluorophenyl)acetyl)hydrazono)acetate (3 g, 11.23 mmol) in a flask was placed in a pre-heated oil bath at 200°C for 15 minutes. The melt was allowed to cool, the resultant solid taken up into MeOH (20 mL), and then the solvent was evaporated. The resultant white solid was suspended in ether (30 mL), stirred for 10 minutes, filtered off, washed with ether (40 mL), and dried under vacuum to give the title compound ethyl 5-(3-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate (1.2 g, 4.81 mmol, 42.9 % yield), which was used without further purification. MS (m/z) 250 (M+H⁺).

The following intermediates used for the preparation of titled example

Preparation 5

5-Benzyl-4H-l,2,4-triazole-3-carboxylic acid

To a solution of ethyl 5-benzyl-4H-l,2,4-triazole-3-carboxylate (8.29 g, 35.85 mmol) in THF (100 mL) was added a solution of LiOH (2.00 g, 84 mmol) in water (20 mL). The mixture was stirred for 20 hours at room temperature. The reaction was concentrated to remove THF and cone. HC1 was added until pH ~ 2 at which point a solid precipitated out. The suspension was stirred for 15 minutes in an ice/water bath, filtered, rinsed with cold water and dried under vacuum to give 6.93 g (80% yield) of 5- benzyl-4H-l,2,4-triazole-3-carboxylic acid hydrochloride. MS (m/z) 204 (M+H⁺).

The following intermediates used for the preparation of titled example compounds were synthesized using methods analogous to the ones described above.

Preparation 6

-(3 -Fluorobenzyl)-4H- 1 ,2,4-triazole-3 -carboxylic

Freshly prepared LiOH (11.03 mL, 22.07 mmol) was added to a stirring, room temperature solution of ethyl 5-(3-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate (1.1 g, 4.41 mmol) in THF (10 mL) under N2. The reaction was then stirred at rt for 5h and LCMS showed the reaction was complete. The reaction was concentrated and then dissolved in 10.0 mL H2O. 2N HCl was added dropwise until the pH= 4. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain title product.5 -(3 -fluorobenzyl)-4H- 1 ,2,4- triazole-3-carboxylic acid (750 mg, 3.39 mmol, 77 % yield). MS (m/z) 222 (M+H⁺).

Preparation 7

Ethyl l-(3-fluorobenzyl)-lH-imidazole-4-carboxylate

To a solution of ethyl lH-imidazole-4-carboxylate (1 g, 7.14 mmol), CS2CO3 (2.56 g, 7.85 mmol) and in DMF (5 mL) was added l-(bromomethyl)-3-fluorobenzene (1.349 g, 7.14 mmol). The reaction mixture was stirred at for 5h. LCMS showed the reaction was completed with product. Added 150 ml of EtOAc and extracted with water, brine and dried over Na2S04. Evaporated all the solvents to afford the crude product as ethyl l-(3-fluorobenzyl)-lH-imidazole-4-carboxylate (1.7 g, 6.85 mmol, 96 % yield). MS (m/z) 250 (M+H⁺). The following intermediates used for the preparation of titled example compounds were sy scribed above.

Preparation 8

l-(3-Fluorobenzyl)-lH-imidazole-4-carboxylic

Freshly prepared LiOH (34.2 mL, 68.5 mmol) was added to a stirring, room temperature solution of ethyl l-(3-fluorobenzyl)-lH-imidazole-4-carboxylate (1.7 g, 6.85 mmol) in THF (25 mL) under N2. The reaction was then stirred at rt overnight and LCMS showed rxn completed. The reaction was concentrated and then dissolved in H2O (10 mL). 2N HC1 was added dropwise until the pH=3. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain title product. l-(3-fluorobenzyl)-lH-imidazole-4-carboxylic acid (1.2 g, 79.5%). MS (m/z) 221 (M+H⁺).

The following intermediates used for the preparation of titled example compounds were sy scribed above.

Preparation 9

Ethyl 5-(4-fluorophenyl)-2,4-dioxopentanoate

To a solution of l-(4-fluorophenyl)propan-2-one (25 g, 164 mmol) diethyl oxalate (28.8 g, 197 mmol) in toluene (300 mL) stirred under nitrogen at 0°C was added KO/-Bu (23.97 g, 214 mmol) in toluene (300 mL). The reaction mixture was stirred at 0°C for 2 more hours and then at rt for over night. LCMS indicated the reaction was completed. Removed all the toluene and dissolved the residue in water and neutralized to pH =6 and extracted with EtOAc twice. The organic phase was combined and washed with brine, and dried over Na2S04. Removed all the solvents to afford the title compound, which was used without further purification (32g, 77%). MS (m/z) 253 (M+H⁺).

The following intermediates used for the preparation of titled example compoun ove.

Preparation 10

Ethyl 5-(4-fluorobenzyl)-lH-pyrazole-3-carboxylate

Hydrazine (1.095 mL, 34.9 mmol) was added to a stirring room temperature solution of ethyl 5-(4-fluorophenyl)-2,4-dioxopentanoate (8 g, 31.7 mmol) in ethanol (100 mL) under N2. The reaction was then heated to reflux (95 C oil bath) until judged complete by HPLC (3h). The reaction was concentrated and purified by silica gel chromatography (solid loading, Isco, 0-45% of EtOAc in hexane). Only pure fractions were combined and concentrated to obtain product as ethyl 5-(4-fluorobenzyl)-lH- pyrazole-3-carboxylate (4 g, 16.11 mmol, 50.8 % yield). MS (m/z) 249 (M+H⁺).

Preparation 11

5-(4-Fluorobenzyl)-lH-pyrazole-3-carboxylic acid

Freshly prepared 2M LiOH aqueous solution (64.5 mL, 129 mmol) was added to a stirring, room temperature solution of ethyl 5-(4-fluorobenzyl)-lH-pyrazole-3- carboxylate (4 g, 16.11 mmol) in THF (65 mL) under N2. The reaction was then stirred at rt for 12 hours and LCMS showed 70% completed. Heated to 50 C for 2h and reaction was completed. The reaction was concentrated and then dissolved in 20 mL H2O. To a stirring aqueous solution, 2N HCl was added dropwise until the pH=4. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight (at 40 °C) to obtain title product as 5-(4- fluorobenzyl)-lH-pyrazole-3-carboxylic acid (3g, 85%). MS (m/z) 221 (M+H⁺). ¾ NMR (DMSO-de) δ: 12.59 - 13.70 (m, 1H), 7.01 - 7.41 (m, 4H), 6.46 (s, 1H), 3.95 (s, 2H).

Preparation 12

-butoxypicolinate

To a mixture of 4-chloropicolinic acid (1 g, 6.35 mmol) and butan-l-ol (5.80 ml, 63.5 mmol) was added sulfuric acid (0.101 ml, 1.904 mmol) and heated to 80 °C for 2 days. After cooling down to rt, the reaction mixture was diluted with water and neutralized with IN NaOH solution to pH 5-6, then extracted with EtOAc (x3). After drying over MgS04, filtration, and evaporation in vacuo, the residue was purified by Biotage (50 g cartridge, 0% to 40% EtOAc in hexane) to give butyl 4-butoxypicolinate (765 mg, 3.04 mmol, 48.0 % yield). MS (m/z) 252.1 (M+H⁺). ¾ NMR (CDCb) δ: 8.55 (d, J = 6.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 5.7, 2.7 Hz, 1H), 4.42 (t, J = 6.8 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 1.77 - 1.87 (m, 4H), 1.43-1.57 (m, 4H), 0.97-1.03 (m, 6H).

Preparation 13

-methyl- 1 -(4-methylbenzyl)- lH-pyrazole-3 -carboxylate

To a solution of ethyl 3-methyl-lH-pyrazole-5-carboxylate (607 mg, 3.94 mmol) in THF (20 mL) was added KOH (221 mg, 3.94 mmol). After stirring for 1 hr at rt, the reaction mixture turned to the suspension, then l-(bromomethyl)-4-methylbenzene (729 mg, 3.94 mmol) was added and heated to reflux. After overnight, the reaction mixture was cooled down to rt and concentrated. The residue was subjected to Biotage (cartridge 50g / pre-wet 5% EtO Ac/Hex / eluent: 5% to 25% EtOAc, then maintained 25% EtO Ac/Hex) to give ethyl 5-methyl-l-(4-methylbenzyl)-lH-pyrazole-3-carboxylate (833 mg, 3.16 mmol, 80 % yield) as a desired product and the regioisomer ethyl 3-methyl-l- (4-methylbenzyl)-lH-pyrazole-5-carboxylate (58 mg, 0.220 mmol, 5.59 % yield). Ethyl 5-methyl-l-(4-methylbenzyl)-lH-pyrazole-3-carboxylate: Ή NMR (CDCb) δ: 7.13 (d, J = 7.1 Hz, 2H), 7.03 (d, 2H), 6.62 (br. s., 1H), 5.36 (br. s., 2H), 4.42 (dd, J = 7.1, 1.3 Hz, 2H), 2.34 (br. s., 3H), 2.19 (s, 3H), 1.35 - 1.50 (m, 3H); MS (m/z) 259.1 (M+H⁺). The regioisomer ethyl 3-methyl-l-(4-methylbenzyl)-lH-pyrazole-5-carboxylate: ¾ NMR (CDCb) d: 7.05 - 7.24 (m, 4H), 6.66 (br. s., 1H), 5.67 (br. s., 2H), 4.19 - 4.42 (m, 2H), 2.32 (d, J = 3.0 Hz, 6H), 1.27 - 1.40 (m, 3H).

The following intermediates used for the preparation of titled example comp

Preparation 14

5- lbenz l)- lH-pyrazole-3-carbox lic

To a solution of ethyl 5-methyl-l-(4-methylbenzyl)-lH-pyrazole-3-carboxylate (830 mg, 3.21 mmol) in THF (3.0 mL) and water (3.0 mL) was added LiOH, HiO (539 mg, 12.85 mmol) at rt. After stirring for overnight at rt, the reaction mixture was concentrated in vacuo. The aqueous solution was diluted with water (5 mL) and acidified with IN HCl (about 5.1 mL) to pH 3-4. The resultant white solid was collected and dried under a vacuum oven to give 5 -methyl- 1 -(4-methylbenzyl)- lH-pyrazole-3-carboxylic acid (670 mg, 2.88 mmol, 90 % yield) as white solids. MS (m/z) 231.1 (M+H⁺). Ή NMR (DMSO-de) d: 12.58 (br. s., 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.51 (s, 1H), 5.32 (s, 2H), 2.27 (s, 3H), 2.22 (s. 3H).

Preparation 15

-benzyl-2H-tetrazole-5-carboxylate

To a solution of ethyl 2H-tetrazole-5-carboxylate, sodium salt (800 mg, 4.85 mmol) in DMF (8 mL) was added (bromomethyl)benzene (1.151 mL, 9.69 mmol) at rt. After stirring for 48 hr at rt, Et3N (1.013 mL, 7.27 mmol) was added to the reaction mixture, then stirred for overnight. After adding water, the reaction mixture was extracted with EtOAc. The combined organic solution was washed with water and brine, dried over MgS04. After filtration and concentration, the residue was subjected to Biotage (50g of silica gel cartridge; eluent: 5% to 15% EtOAc, then maintained 15% EtO Ac/Hex) to give ethyl 2-benzyl-2H-tetrazole-5-carboxylate (342 mg, 1.473 mmol, 30.4 % yield, unoptimized) as a major product: MS (m/z) 233.1 (M+H⁺); 'H NMR (DMSO-de) d: 7.36 - 7.46 (m, 5H), 6.05 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.33 (t, 3H). The regioisomer ethyl 1 -benzyl- lH-tetrazole-5-carboxylate (87 mg, 0.375 mmol, 7.73 % yield) was obtained as a minor product: Ή NMR (DMSO-de) d: 7.29 - 7.43 (m, 5H),

5.92 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.33 (t, 3H) (Note: some mixture of both products was also obtained).

The following intermediate used for the preparation of titled example compounds was synthesized using methods analogous to the ones described above.

Preparation 16

2-Benzyl-2H-tetrazole-5 -carboxylic acid

To a solution of ethyl 2-benzyl-2H-tetrazole-5-carboxylate (338 mg, 1.455 mmol) in THF (3 mL) and water (3.00 mL) was added LiOH (183 mg, 4.37 mmol). After stirring for lhr at rt, the reaction mixture was concentrated in vacuo and the residual aqueous solution was acidified with IN HCl (around pH -2-3). A small amount of white solids was precipitated out. After collecting solids, the aqueous solution was placed in a hood and allowed to slow evaporation of water. Another white solid was obtained (followed this step two more times. Note: some product was still detected in water). The combined solid was dried in a vacuum oven at 50 °C to give 2-benzyl-2H-tetrazole-5- carboxylic acid (167.4 mg, 0.820 mmol, 56.3 % yield) as white solids. MS (m/z) 205.0 (M+H⁺). Ή ΝΜΡν (DMSO-de) δ: 14.30 (br. s., 1H), 7.33 - 7.49 (m, 5H), 6.03 (s, 2H).

Preparation 17

Ethyl 5-(difluoro(phenyl)methyl)isoxazole-3-carboxylate

Ethyl 5-benzoylisoxazole-3-carboxylate (630 mg, 2.57 mmol) was dissolved in 2 mL of DCE, and then a solution of DAST (0.944 mL, 7.71 mmol) in 2 mL of DCE was added dropwise at 0 °C. The reaction mixture was maintained at 50 °C for 16 h, and then the mixture was concentrated. The resulting brown residue was purified by Isco

Combiflash (10 %-30 % EtOAc/Hexane; 80 g Isco RediSep column). Collected fractions containing the product were combined and concentrated to give the desired product as a yellow oil (207 mg, 31 % yield). 'H NMR (CDCb) δ ppm 7.56 - 7.64 (m, 2H), 7.45 - 7.56 (m, 3H), 6.87 (s, 1H), 4.45 (q, J = 7.2 Hz, 4H), 1.41 (t, J = 7.1 Hz, 3H); MS (m/z): 268 (M+H⁺).

Preparation 18

5 -

Ethyl 5-(difluoro(phenyl)methyl)isoxazole-3-carboxylate (207 mg, 0.775 mmol) was dissolved in 2 mL of THF, and then LiOH monohydrate (48.8 mg, 1.162 mmol) was added. The reaction mixture was maintained at rt for 16 h. The rxn mixture was neutralized by adding a solution of 4N HCl/dioxane dropwise. The mixture was then filtered and the filtrate was concentrated to a yellow oil (185 mg, 100 % yield). MS (m/z): 240 (M+H⁺).

Preparation 19

5 )methyl)isoxazole-3 -carboxylic acid

Ethyl 5-benzoylisoxazole-3-carboxylate (400 mg, 1.631 mmol) was dissolved in 5mL MeOH, and then NaBH₄ (93 mg, 2.447 mmol) was added at 0 °C. The reaction mixture was maintained at rt for 16 h. The mixture was concentrated, and then partitioned between sat. NaHC03(aq) and DCM. The organic layer was concentrated and dissolved in lmL THF. An aqueous solution of LiOH (1.2 mL, 50 mg/ml solution) was added to this THF solution. The mixture was maintained at rt for 16 h. A solution of HCl (0.8 mL, 4N in dioxane) was added to the mixture. The organic layer was separated and concentrated to a yellow oil (190 mg, 53 % yield). ¾ NMR (DMSO-de) δ ppm 7.26 - 7.54 (m, 6H), 6.50 (s, 2H), 5.91 (s, 1H); MS (m/z): 220 (M+H⁺). Preparation 20

Ethyl 5 -benzylisoxazole -3 -carboxylate

A solution of the ethyl 2-chloro-2-(hydroxyimino)acetate (39.1 g, 258 mmol) was dispensed into a solution of prop-2-yn-l-ylbenzene (10 g, 86 mmol) and triethylamine (29.4 mL, 430 mmol) in CH3CN (300 mL). After standing for overnight at 80 °C the solvent was removed in vacuum. The crude was dissolved in EtOAc (200 mL) and was washed with saturated NaHCC solution (50 mL), water (50 mL) and saturated brine (50 mL). The organic phase was separated and dried over sodium sulphate and evaporated in vacuo to give ethyl 5 -benzylisoxazole-3 -carboxylate (6 g, 25.9 mmol, 30 % yield) as a yellow solid. Used directly in the next step without further purification. MS (m/z): 232

(M+H⁺).

Preparation 21

5 -Benzylisoxazole-3 -carboxylic acid

A solution of the ethyl 5-benzylisoxazole-3-carboxylate (6 g, 25.9 mmol) was dispensed into a solution of the NaOH (2.1 mL, 78 mmol) in MeOH (100 mL) and water (10 mL). After standing for 2 h at 20 °C, the solvent was removed in vacuum. The residue was acidified with dilute HC1 (20 mL) and then extracted with EtOAc (50 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), and dried over sodium sulphate. Evaporation in vacuo gave 5-benzylisoxazole-3-carboxylic acid (3.2 g, 15.31 mmol, 59.0 % yield) as a yellow solid. ¾ NMR (DMSO-de) δ ppm 14.0 (bs, 1H), 7.2 - 7.4 (m, 5H), 6.6 (s, 1H), 4.2 (s, 2H); MS (m/z): 204 (M+H⁺). Preparation 22

5-(4-Chlorobenzyl)isoxazole-3-carboxylic

Me0₂C-C0₂ e

HO-NH₂

EtOH

To a solution of l-(4-chlorophenyl)propan-2-one (10 g, 59.3 mmol) in THF (150 mL) in an ice bath was added NaH (1.423 g, 59.3 mmol) portion wise over 30min. Dimethyl oxalate (7.0 g, 59.3 mmol) was added at room temperature for lhour and the mixture was stirred at 25 °C for 2 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc which was washed with water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were dried over Na2S04, filtered, and concentrated in vacuo to give methyl 5-(4-chlorophenyl)-2,4- dioxopentanoate (15g, 50.1 mmol, 84 % yield) as an oil which was used in next step without further purification. MS (m/z): 255/257 (M+H⁺).

To a solution of methyl 5-(4-chlorophenyl)-2,4-dioxopentanoate (5 g, 19.63 mmol) in ethanol (80 mL) was added hydroxylamine hydrochloride (1.364 g, 19.63 mmol) and then the mixture was stirred at 78 °C for 2 hours monitored. The solvent was removed in vacuo and the residue was dissolved in EtOAc which was washed with water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were dried over Na2S04, filtered, and concentrated in vacuo to give methyl 5-(4-chlorobenzyl)isoxazole-3-carboxylate (4.7 g, 16.81 mmol, 86 % yield) as a solid, which was used in next step without further purification. MS (m/z): 252/254 (M+H⁺).

To a solution of methyl 5-(4-chlorobenzyl)isoxazole-3-carboxylate (100 mg,

0.397 mmol) in THF (5 mL) in an ice bath was added a solution of NaOH (15.89 mg, 0.397 mmol) in water (5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in water. The aqueous solution was acidified by addition of IN HC1 to pH=2-3. The resulting solid which deposited was collected by filtration and dried in vacuo to give pure 5-(4- chlorobenzyl)isoxazole-3-carboxylic acid (90 mg, 0.360 mmol, 91 % yield) as solid. MS (m/z): 238/240 (M+H⁺).

Preparation 23

5-((Methyl(phenyl)amino)methyl)-lH-pyrazole-3-carboxylic acid

To a mixture of ethyl l-acetyl-5-methyl-lH-pyrazole-3-carboxylate (2 g, 10.19 mmol) and NBS (1.996 g, 11.21 mmol) in CC (20 mL) was added benzoic

peroxyanhydride (0.123 g, 0.51 mmol) at room temperature followed by reflux for 5 hours. LCMS showed product with some starting material left. Removed all the solvent and the residue was purified by flash chromatography by solid loading (e luting 0-30% of EtOAc in hexane) to afford the product. Combined the fractions and removed all the solvents to afford the crude product as ethyl l-acetyl-5-(bromomethyl)-lH-pyrazole-3- carboxylate (1.6 g, 5.82 mmol, 57.1 % yield) MS (m/z) 232 /234 (M + H⁺, - Acetyl) To a solution of N-methylaniline (42.9 mg, 0.4 mmol) in DMF (2 mL) at 20°C was added NaH (21.84 mg, 0.546 mmol). The reaction mixture was stirred for 5 min. Then ethyl l-acetyl-5-(bromomethyl)-lH-pyrazole-3-carboxylate (100 mg, 0.364 mmol) was added and the mixture were stirred at room temperature for 3 more hours. LCMS indicated the reaction was completed. The reaction was quenched with drop of water and the solvents were removed to dryness. The crude ethyl l-acetyl-5- ((methyl(phenyl)amino)methyl)-lH-pyrazole-3-carboxylate (100 mg, 91%) was used for hydrolysis without further purification. MS (m/z) 260 (M + H⁺ - Acetyl).

To a solution of ethyl l-acetyl-5-((methyl(phenyl)amino)methyl)-lH-pyrazole-3- carboxylate (110 mg, 0.365 mmol) in THF (2 mL) was added a solution of LiOH (1.825 mL, 3.65 mmol) in water (1.0 mL) . The reaction mixture was stirred at room temperature for 16 hours and then heated to 50°C for 4 h at which time LCMS showed hydrolysis was completed. Cooled to 0°C and added IN HCl until pH=2. The resulting solid was filtered and dried under vacuum. The 5 -((methyl (phenyl)amino)methyl)-lH- pyrazole-3-carboxylic acid (80mg, 95%) was used as such without further purification. MS (m/z) = 231 (M + H⁺)

Example 1

(<S)-Benzyl (3-hydroxy- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-2- yl)carbamate

To a stirring 0°C solution of 2-(methylamino)phenol (389 mg, 3.16 mmol) (S)-2- (((benzyloxy)carbonyl)amino)-3-hydroxypropanoic acid (755 mg, 3.16 mmol), 2- (methylamino)phenol (389 mg, 3.16 mmol) and diisopropylethylamine (1102 μΐ, 6.31 mmol) in isopropanol (8.6mL) was added 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (2818 μΐ, 4.73 mmol). After 2 m, the reaction was partitioned between EtOAc and water, the aqueous layer was back extracted with EtOAc and the pooled organics were washed with brine, dried over anhydrousMgS04 and concentrated in vacuo to an oil. The oil was purified via Isco CombiFlash Rf (25% to

100% in EtOAc in Hexanes; 40g silica gel cartridge column). The desired fractions were concentrated in vacuo to give (<S)-benzyl (3 -hydroxy- 1 -((2- hydroxyphenyl)(methyl)amino)-l-oxopropan-2-yl)carbamate (581 mg, 54% yield) as a white solid. ¾ NMR (400 MHz, CDCb) δ ppm 7.41 (m, 5 H); 7.07 - 7.17 (m, 1 H); 6.86 - 7.05 (m, 1 H); 6.10 (m, 1 H) 5.90 (m, 1 H) 5.11 (s, 2 H) 4.94 - 5.09 (m, 1 H) 4.38 - 4.54 (m, 1 H); 4.05 (m, 1 H); 3.82 (m, 1 H) 3.71 - 3.81 (m, 2 H); 3.20 (s, 3 H). MS (m/z) 345.2 (M+H⁺).

Example 2

(<S)-fert-Butyl (3 -hydroxy- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-

To a cloudy solution of (5)-2-((fert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (257 mg, 1.253 mmol) in ethyl acetate (6 mL) was added DIEA (0.438 mL, 2.506 mmol) and 2-(methylamino)phenol hydrochloride (100 mg, 0.627 mmol) and mixture was stirred for 1 minute. Mixture was slightly cloudy and light yellow. Then propylphosphonic anhydride (T3P) (50% in EtOAc) (0.746 mL, 1.253 mmol) was added quickly dropwise. The reaction was mildly exothermic. Reaction was stirred at room temperature for 1.5 hours and then diluted with EtOAc and satd. NaHCC . The layers were separated and organics were washed with satd. NaHCC , water and brine.

Organics were concentrated and purified by ISCO (4 g silica column; 5-50%

EtOAc/Hexanes, 8 min.; 50%, 5 min.) to give 80 mg off-white foam in 41% yield. MS (m/z) 311 (M+H⁺). NMR most likely contained rotomers at room temperature. Ή NMR (DMSO-de) δ: 9.86 (br. m., 1H), 7.22 (m, 2H), 6.97 (m, 1H), 6.87 (m, 1H), 6.56 (d, 0.65H), 6.19 (d, 0.35H), 4.72 (m, 0.35H), 4.53 (br. s., 0.65 H), 4.11 (m, 1H), 3.40 (m, 1H), 3.26 (m, 1H), 3.06 (d, 3H), 1.36 (d, 9H).

Example 3

(<S)-fert-Butyl (3 -(i-butoxy)- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-2 -

To a solution of 2-(methylamino)phenol hydrochloride (0.4 g, 2.506 mmol) in /-propanol (21.26 ml) was added DIPEA (1.563 ml, 8.77 mmol) at rt. After stirring for 15 min, (5)-3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.85 g, 3.19 mmol) was added. After cooling down to 0 °C, 2,4,6-tripropyl- 1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (T3P) (2.238 ml, 3.76 mmol) was added, then warmed up to RT while stirring for 4 hr. The reaction was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NaHCC solution, then brine. The aqueous layer was extracted with EtOAc. The combined organic solution was dried over Na2S04, filtered, and concentrated. The crude was purified via Biotage (SNAP Cartridge KP Sil 50 g, 10 - 30% EtOAc/Hexane) to yield

(3-(fert-butoxy)-l-((2- hydroxyphenyl)(methyl)amino)-l-oxopropan-2-yl)carbamate (0.82 g, 2.238 mmol, 89 % yield). ¾NMR (600 MHz, DMSO- 6) δ (ppm): 0.89 - 1.05 (m, 9 H), 1.30 - 1.41 (m, 9 H), 3.00 - 3.07(m, 3 H), 3.10 - 3.17 (m, 1 H), 3.35 (br. s, 1 H), 4.08 - 4.21 (m, 1 H), 6.19 - 6.72 (m, 1 H), 6.81 - 6.91 (m, 1 H), 6.94 - 7.01 (m, 1 H), 7.16 - 7.26 (m, 2 H), 10.02

(br. s, 1 H). MS: m/z: 367.3 [M+H]⁺.

Example 4

(5)-2-Amino-3-hy de Hydrochloride

4Ν HQ in dioxane (6.69 mL, 26.7 mmol) was added to (<S)-fert-butyl-(3-(fert- butoxy)-l-((2-hydroxyphenyl)(methyl)amino)-l-oxopropan-2-yl)carbamate (0.98 g, 2.67 mmol). The reaction mixture was stirred at RT for 18 hr. Off-white solid that precipitated from the reaction, was filtered and washed with dichloromethane, azeotropically dried by toluene (x 3) to yield (<S)-2-amino-3-hydroxy-N-(2-hydroxyphenyl)-N- methylpropanamide hydrochloride (0.522 g, 2.116 mmol, 79% yield). ¾ NMR (400

MHz, DMSO- 6) δ (ppm): 3.10 (d, J=8.84 Hz, 3 H), 3.54 (d, J=11.37 Hz, 1 H), 3.56 - 3.63 (m, 1 H), 3.74 (dd, J=8.34, 3.54 Hz, 1 H), 5.27 - 5.44 (m, 1 H), 6.86 - 6.96 (m, 1 H), 7.09 (d, J=8.08 Hz, 1 H), 7.21 - 7.37 (m, 2 H), 8.23 (br. s, 2 H), 10.32 (br. s., 1 H). MS: m/z: 211.0 [M+H]⁺. Example 5

(5)- -Hydroxy-N-(2-hydroxyphenyl)-N-methyl-2-(tritylamino) propanamide

To a solution of (<S)-2-amino-3-hydroxy-N-(2-hydroxyphenyl)-N- methylpropanamide hydrochloride (2.0 g, 8.11 mmol) in dry chloroform (100 mL) at 0 °C were slowly added Et₃N (4.52 mL, 32.4 mmol) and Ph₃CCl (3.39 g, 12.17 mmol). The mixture was stirred at 0 °C for 3 hr. Removed all the solvents under reduced pressure. The residue was dissolved in 100 ml of EtOAc and washed NaHCC (2 x 50 ml) and brine (50 ml). The organic phase was dried over MgSCk The solvent was removed under reduced pressure to provide the crude (<S)-3-hydroxy-N-(2- hydroxyphenyl)-N-methyl-2-(tritylamino) propanamide (3.67 g, quantitative) as orange solid which was used without further purification. MS (M+H)⁺ = 453. ¾ NMR (CDCb) δ (ppm): 7.42-7.54 (m, 1H), 7.30-7.39 (m, 15H), 6.90-7.23 (m, 2H), 5.30-5.63 (m, 1H), 4.15-4.25 (m., 2H), 3.80-3.90 (m, 1H), 2.87 (s, 3H).

Example 6

(5)-3 amide

To a solution of (5)-3-hydroxy-2-(tritylamino)propanoic acid (5 g, 14.39 mmol) in isopropanol (50 mL) stirred under nitrogen at 0 °C was added DIEA (5.03 mL, 28.8 mmol) stirred it for 10 min, then added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (18.32 g, 28.8 mmol) at the same temperature. After 10 min,

2-(methylamino)phenol (1.772 g, 14.39 mmol) was added and continued to stir at room temperature for 16 hr. Reaction mixture was concentrated over the rotavapour and the residue was diluted with water (40 mL) and extracted with EtOAc (3x30 mL), then washed with brine (25 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure followed by purification by column chromatography using silica gel 100-200 mesh, eluted with 10-40% EtOAc in hexane to provide (¾-3-hydroxy-N-(2-hydroxyphenyl)-N-methyl-2-(tritylamino)propanamide (700 mg, 1.329 mmol, 9.23 % yield) as colourless solid. See Example 5 for LCMS and ¾ NMR data. Example 7

(<S)-B -2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate

A solution of (<S)-benzyl (3-hydroxy-l-((2-hydroxyphenyl)(methyl)amino)-l- oxopropan-2-yl)carbamate (350 mg, 1.016 mmol), triphenylphosphine (400 mg, 1.525 mmol) and diethylazodicarboxylate (603 μΐ, 1.525 mmol) in toluene (9560 μΐ) was stirred for 5 m at 25°C, and then concentrated in vacuo to an oil. The crude oil was purified via Isco CombiFlash Rf (10% to 100% in EtOAc in Hexanes; 40g silica gel cartridge column) and the desired fractions were pooled and concentrated in vacuo to give (<S)-benzyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3- yl)carbamate (60mg, 18% yield) as a colorless oil. ¾ NMR (400 MHz, DMSO- 6) δ ppm 7.69 (d, J= 8.59 Hz, 1 H); 7.48 (dd, J= 7.71, 1.64 Hz, 1 H); (7.24 -7.40 (m, 7 H); 7.17 - 7.22 (m, 1 H); 4.99 (d, J= 1.77 Hz, 2 H); 4.38 - 4.46 (m, 1 H); 4.25 - 4.38 (m, 2 H); 3.29 (s, 3 H). MS (m/z) 327.2 (M+H⁺).

Example 8

(5)-fert-Butyl-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3- yl)carbamate

To a solution of (<S)-fert-butyl (3-hydroxy-l-((2-hydroxyphenyl)(methyl)amino)- l-oxopropan-2-yl)carbamate (100 mg, 0.322 mmol) in toluene (4 mL) was added triphenylphosphine (PPI13) (169 mg, 0.644 mmol). Heated mixture to 100°C and then added diethyl azodicarboxylate (DEAD) (40% by wt in toluene) (0.293 mL, 0.644 mmol) dropwise. The mixture was heated at 100°C for 10 minutes. The reaction was concentrated and purified by ISCO (4g silica column; 5-30% EtOAc/Hexanes, 10 min.; 30%, 5 min) to give 41 mg tan solid in 43% yield. MS (m/z) 293 (M+H⁺). Ή NMR (DMSO-de) δ: 7.47 (dd, J=7.8, 1.8 Hz, 1H), 7.23-7.34 (m, 2H), 7.13-7.21 (m, 2H), 4.26- 4.40 (m, 3H), 3.28 (s, 3H), 1.34 (s, 9H).

Example 9

(5)-5-Methyl-3-(tritylamino)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-

To a solution of (<S)-3-hydroxy-N-(2-hydroxyphenyl)-N-methyl-2- (tritylamino)propanamide (1.5 g, 3.31 mmol) in toluene (50 mL) under Ν2 at 0 °C was added triphenylphosphine (1.521 g, 5.80 mmol) and stirred for 10 min, then added (E)- diethyl diazene-l,2-dicarboxylate (DEAD) (2.64 mL, 5.80 mmol, 40% wt in toluene). The mixture was stirred at 0 °C for 0.5 hr and then warmed up to room temperature and continued to stir for 5 hr. The mixture was diluted with EtOAc (300 ml) and the organic phase was washed with water (2 x 100 ml) and brine (200 ml). The organic layer was separated and dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by ISCO (eluting 0-5% of EtOAc in hexane) to afford the product (iS)-5-methyl-3-(tritylamino)-2, 3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one as light yellow solid (1.0 g, 69.4%). MS (M+H)⁺ = 435. ¾ NMR (600 MHz, DMSO-de) δ (ppm): 2.79 (s, 3 H), 3.18 (d, J=8.69 Hz, 1 H), 3.42 (d, J=8.69 Hz, 1 H), 4.30 (t, J=10.76 Hz, 1 H), 4.36 - 4.43 (m, 1H), 7.04 - 7.08 (m, 1 H), 7.10 - 7.15 (m, 2 H), 7.18 (t, J=6.99 Hz, 4 H), 7.22 - 7.30 (m, 12 H).

Example 10

(<S)-fert-Butyl (3-(fert-butoxy)- 1 -((2-fluorophenyl)amino)- 1 -oxopropan-2-yl)carbamate

To a solution of (5)-3-(feri-butoxy)-2-((feri-butoxycarbonyl)amino)propanoic acid (8.0 g, 30.6 mmol) in EtOAc (250 mL) were added 2-fluoroaniline (3.55 mL, 36.7 mmol) and ;^'-Pr₂NEt (10.69 mL, 61.2 mmol). The solution was cooled in an ice/water bath and propylphosphonic anhydride (T3P) (50% in EtOAc) (27.3 mL, 45.9 mmol) was added dropwise over 10 min. Ice bath was removed and reaction was stirred at room temperature for 18 hr. The reaction mixture was washed with 1M HC1 (2x), satd. aq. NaHCC>3 (2x), water, and brine. Organics were concentrated and dried to give 9.16 g of white solid in 84% yield. ¾ NMR (CDCb) δ (ppm): 9.05 (br. s, 1H), 8.36 (t, J=8.1 Hz, 1H), 7.03-7.18 (m, 3H), 5.56 (br. s., 1H), 4.36 (br. s, 1H), 3.91 (br. s, 1H), 3.47 (t, J=8.5 Hz, 1H), 1.50 (s, 9H), 1.28 (s, 9H); MS (m/z) 355.2 (M+H⁺).

Example 1 1

(<S)-fert-Butyl (3 -(fert-butoxy)- 1 -((2-fluorophenyl)(methyl)amino)- 1 -oxopropan-2- yl)carbamate

Method A

To a solution of (S)-te rt-butyl (3-(teri-butoxy)-l-((2-fluorophenyl)amino)-l- oxopropan-2-yl)carbamate (7.08 g, 19.98 mmol) in DMF (150 mL) were added cesium carbonate (8.46 g, 26.0 mmol) and iodomethane (1.374 mL, 21.97 mmol). Reaction was stirred at room temperature for 18 hours, and then diluted with hexanes and water. Layers did not totally separate, so mixture was run through a small plug of Celite, rinsing with hexanes and water. Layers of filtrate were separated and organics were washed with brine and concentrated to give 6.68 g of light yellow cloudy thick oil in 91% yield. MS (m/z) 355.2 (M+H⁺). ¾ NMR was run at an elevated temperature to eliminate rotomers. ¾ NMR (DMSO- e) (at 80 °C) δ: 7.40-7.48 (m, 2H), 7.25-7.35 (m, 2H), 6.17 (br. s., 1H), 4.25 (br. s., 1H), 3.43 (br. s., 1H), 3.26 (br. s., 1H), 3.19 (s, 3H), 1.37 (s, 9H), 1.07 (s, 9H).

Method B

Coupling Method I (T₃P):

To a solution of 2-fluoro-N-methylaniline (110 mg, 0.879 mmol) in

dichloromethane (5 mL) was slowly added (S)-3-(tert-butoxy)-2-((tert- butoxycarbonyl)amino)propanoic acid (253 mg, 0.967 mmol), 2,4,6-tripropyl-

1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.570mL, 2.64 mmol, 50% in ethyl acetate) and N-ethyl-N-isopropylpropan-2 -amine (0.461 mL, 2.64 mmol). The reaction mixture was stirred at room temperature overnight (still starting material remained). Removed solvent and the residue was purified by silica gel column chromatography (Biotage, eluent: 0 to 10% EA/Hexane) to provide (<S)-fert-butyl (3-(tert-butoxy)-l-((2- fluorophenyl)(methyl)amino)-l-oxopropan-2-yl)carbamate (108 mg, 0.293 mmol, 33.3 % yield). The structure was confirmed by LCMS and 1H NMR, which was identical to the product from Method A. Coupling Method II (isobutyl chloroformate):

To a solution of (5)-3-(feri-butoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (689 mg, 2.64 mmol) in dichloromethane (4 mL) was added N-methylmorpholine (0.387 mL, 3.52 mmol) followed by isobutyl chloroformate (0.346 mL, 2.64 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 10 min. A separately prepared solution of 2-fluoro-N-methylaniline (0.100 mL, 0.879 mmol) and 0.097 mL of N-methylmorpholine in 0.5 ml of dichloromethane was added to the above reaction mixture at once. The reaction was allowed to warm to room temperature and stirred overnight. Removed solvent and the residue was purified by silica gel column chromatography to provide

(3-(tert-butoxy)-l-((2- fluorophenyl)(methyl)amino)-l-oxopropan-2-yl)carbamate (219 mg, 0.535 mmol, 60.9 % yield). The structure was confirmed by LCMS and 1H NMR, which was identical to the product from Method A.

Example 12

(5)-2-Amino drochloride

To a solution of (S)-te rt-butyl (3-(fert-butoxy)-l-((2- fluorophenyl)(methyl)amino)-l-oxopropan-2-yl)carbamate (5.98 g, 16.23 mmol) in dichloromethane (DCM) (80 mL) was added HCI (4M in dioxane) (20.29 mL, 81 mmol). Reaction was stirred at room temperature for 18 hours. More HCI (4M in dioxane) (5 mL) was added and reaction was stirred for another 24 hours. A white solid had precipitated out, and it was filtered, rinsing with DCM and Et20, and dried to give 3.66 g of a hygroscopic, off-white solid in 90% yield. MS (m/z) 213.0 (M+H⁺). Ή NMR was run at an elevated temperature to eliminate rotomers. ¾ NMR (DMSO-cfe) (at 90 °C) δ: 7.38-7.48 (m, 2H), 7.24-7.35 (m, 2H), 4.21 (br. s., 1H), 3.40-3.48 (m, 1H), 3.35 (br. s., 1H), 3.20-3.27 (m, 1H), 3.18 (s, 3H), 1.52 (br. s., 2H).

Example 13

(5)-N-(2 anamide

To a suspension of (<S)-2-amino-N-(2-fluorophenyl)-3-hydroxy-N- methylpropanamide, Hydrochloride (1.00 g, 4.02 mmol) in chloroform (40 mL) was added TEA (1.233 mL, 8.85mmol). The mixture became homogeneous and was cooled in an ice/water bath. (Chloromethanetriyl)tribenzene (1.177 g, 4.22 mmol) was added, ice bath was removed and reaction was stirred for 1.5 hours. The reaction was diluted with satd. NaHCC and layers were separated. Organics were washed with water and brine and concentrated to a sticky semi solid. Hexanes were added, followed by a small amount of EtOAc. Flask was scraped with a spatula and then the mixture was stirred vigorously and some solid formed. Mixture was concentrated to a white solid, triturated in 5% EtOAc/hexanes, filtered and dried to give 1.50 g of white solid in 82% yield. MS (M+H)⁺ = 455. ¾ NMR was run at an elevated temperature to eliminate rotomers. ¾ NMR (DMSO- e) (at 120 °C) δ: 7.40 (m, 6H), 7.11-7.32 (m, 12H), 7.06 (t, J=7.4 Hz, 1H), 6.73 (br. s., 1H), 4.16 (br. s., 1H), 3.58 (br. s., 1H), 3.35 (br. s., 1H), 3.28 (d, J=7.9 Hz, 2H), 2.96 (s, 3H)

Example 14

(5)-5 H)-

Dissolved (<S)-N-(2-fluorophenyl)-3-hydroxy-N-methyl-2- (tritylamino)propanamide (30mg, 0.066 mmol) in DMF (1 mL) at room temperature, added cesium carbonate (75 mg, 0.231 mmol) and stirred at room temperature for 1 hour followed by heating at 50 °C for 7 days. Reaction was diluted with water and hexanes and layers were separated. Washed organics with brine and concentrated. Some product remained in aqueous (aqueous layer was cloudy and white). Aqueous was extracted with Et20 and organics were washed with brine. Concentrated and dried organics to give 26 mg of white foam in 86% yield. LCMS showed (M+H)⁺ = 243 (trityl cation). ¾ NMR was the same as for the product in Example 9.

Example 15

(<S)-3 -Amino-5 -methyl-2,3 -dihydrobenzo [b] [ 1 ,4]oxazepin-4(5H)-one hydrochloride

To a solution of (5)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][l,4]oxazepin- 4(5H)-one (75 mg, 0.173 mmol) in 1,4-dioxane (3 mL) were added 4N HCI in dioxane (0.173 mL, 0.518 mmol) and MeOH (0.5 mL) under nitrogen at rt. The mixture was stirred for 15 hr at rt. Removed all the solvents and washed the resulting solid with Et20 (2x 5 mL) to provide (5)-3-amino-5-methyl-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)- one hydrochloride (40 mg, 0.173 mmol, quantitative) which was used without further purification. MS (M+H)⁺ = 193. ¾ NMR (DMSO- e): δ (ppm): 8.47 (br. s, 2H), 7.47- 7.67 (m, 1H), 7.20-7.43 (m, 2H), 4.54-4.68 (m, 1H), 4.44 (t, J=10.5 Hz, 1H), 4.22-4.36 (m, 1H), 3.29-3.45 (m, 3H).

Example 16

(¾-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)-4H- l,2,4-triazole-3-carboxamide

To a solution of (5)-3-amino-5-methyl-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)- one hydrochloride (100 g, 437 mmol), 5-benzyl-4H-l,2,4-triazole-3-carboxylic acid hydrochloride (110 g, 459 mmol) in DCM (2.5 L) was added DIPEA (0.267 L, 1531 mmol) at 15 °C. The reaction mixture was stirred for 10 min. and 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide >50 wt. % in EtOAc (0.390 L, 656 mmol) was slowly added at 15 °C. After stirring for 60 mins at RT the LCMS showed the reaction was complete, upon which time it was quenched with water, partitioned between DCM and washed with 0.5N HC1 aq (2 L), saturated aqueous NaHCC (2 L), brine (2 L) and water (2 L). The organic phase was separated and activated charcoal (100 g) and Na2S04 (200 g) were added. The dark solution was shaken for 1 h before filtering. The filtrate was then concentrated under reduced pressure to afford the product as a tan foam (120 g). The product was dried under a high vacuum at 50 °C for 16 h. ¾ NMR showed 4-5% wt of ethyl acetate present. The sample was dissolved in EtOH (650 ml) and stirred for 30 mins, after which the solvent was removed using a rotavapor (water-bath T=45 °C). The product was dried under high vacuum for 16 h at RT (118 g, 72% yield). The product was further dried under high vacuum at 50 °C for 5 h. ¾ NMR showed <1% of EtOH and no ethyl acetate. ¾ NMR (400 MHz, DMSO- e) δ ppm 4.12 (s, 2 H), 4.31 - 4.51 (m, 1 H), 4.60 (t, J=10.36 Hz, 1 H), 4.83 (dt, J=l 1.31, 7.86 Hz, 1 H), 7.12 - 7.42 (m, 8 H), 7.42 - 7.65 (m, 1 H), 8.45 (br. s., 1 H), 14.41 (br. s., 1 H). MS (m/z) 378 (M + H⁺).

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.

Claims

We claim:

1. A process for preparing a benzoxazepine of

Formul

wherein:

ZUs CH or CR¹;

Z² is CH or CR²;

Z³ is CH or CR³;

Z⁴ is CH or CR⁴;

R¹ is fluoro or methyl;

one of R² and R³ is halogen, cyano, (Ci-Ce)alkyl, halo(Ci-C4)alkyl,

(Ci-C₆)alkoxy, halo(Ci-C₄)alkoxy, hydroxyl, B(OH)₂, -COOH,

halo(Ci-C4)alkylC(OH)₂-, (Ci-C4)alkoxy(Ci-C4)alkoxy, (Ci-C₄)alkylS02-,

(Ci-C4)alkoxy(C₂-C4)alkylNHC(0)NH-, (Ci-C4)alkylS0₂(C₂-C4)alkylNHC(0)-,

(Ci-C4)alkylNHC(0)NH-, (Ci-C4)alkylOC(0)NH-, hydroxy(Ci-C4)alkylOC(0)NH-, 5-6 membered heterocycloalkyl-C(O)-, 5-6 membered

heterocycloalkyl-(Ci-C4)alkyl-NHC(0)-, 5-6 membered

wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (Ci-C4)alkyl and -(Ci-C4)alkyl-CN; and the other of R² and R³ is halogen or (Ci-Ce)alkyl;

4 is fluoro, chloro, or methyl;

wherein:

A is phenyl, 5-6 membered heteroaryl, or 5-6 membered

heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on

ring A;

m is 0 or m is 1 and R^A is (Ci-C4)alkyl; and

L is O, S, NH, N(CH₃), CH₂, CH2CH2, CH(CH₃), CHF, CF₂, CH2O,

CH₂N(CH₃), CH2NH, or CH(OH); and

B is an optionally substituted (C3-Ce)cycloalkyl, phenyl, 5-6

membered heteroaryl, or 5-6 membered heterocycloalkyl;

wherein said (C3-C6)cycloalkyl, phenyl, 5-6 membered heteroaryl, or

5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or

two substituents each independently selected from halogen, (Ci-C4)alkyl,

halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, nitro, and

(Ci-C₄)alkylC(0)-;

or the moiety -L-B is (C3-Ce)alkyl, (C3-Ce)alkoxy, halo(C3-Ce)alkoxy,

(C3-C6)alkenyl, or (C3-Ce)alkenyloxy;

or a salt thereof;

wherein the process comprises converting a substituted (¾i-3-hydroxy-N-methyl-

2-aminopropanamide compound having Formula (II):

wherein W is OH or fluoro and R^p is an amine protecting group, into a 2,3- dihydrobenzo [b] [ 1 ,4] oxazepin-4(5H)-one compound having Formula (IV) :

2. The process according to claim 1, wherein the process comprises:

1) cyclizing the compound of Formula (II) to form a 2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one compound having Formula (III):

2) converting the compound of Formula (III) into the compound of Formula (IV).

3. The process according to claim 2, further comprising reacting the compound of Formula (IV) with a compound of Formula (V),

to form the compound of Formula (I), or a salt thereof.

4. The process according to any one of claims 1-3, further comprising converting an aniline compound of Formula

into an amide compound of Formula (II-C):

by treating the compound of Formula (Π-Α) with a compound of Formula (II -B):

wherein R^PA is an amine protecting group and R^X is H or R^PH, wherein R^PH is a hydroxyl protecting group.

5. The process according to claim 4, further comprising converting the amide compound of Formula (II-C) into an amino-amide compound of Formula (II-D):

6. The process according to claim 5, further comprising converting the compound of

7. The process according to claim 6, further comprising converting the compound of Formula (Π-Ε) into the compound of Formula (I).

8. The process according to any one of claims 4-7, wherein R^PA is a Boc group.

9. The process according to any one of claims 4-8, wherein R^p is a trityl group.

10. The process according to any one of claims 4-9, wherein R^x is H. 11. The process according to any one of claims 4-9, wherein R^x is R^PH.

12. The process according to claim 11, wherein R^PH is a fert-butyl group.

13. The process according to any one of claims 1-3, further comprising converting the compound of Formula (II-K) :

into an amide compound of Formula (II-L):

by treating the compound of Formula (II-K) with a compound of Formula (II -B) :

14. The process according to claim 13, further comprising converting the compound of Formula (II-L) into an alkylated compound of Formula (II -M):

15. The process according to claim 14, further comprising converting the compound of Formula (II-M) into an amino-amide compound of Formula (II -N):

16. The process according to claim 15, further comprising converting the compound of Formula (II-N) into the compound of Formula (Π-0),

17. The process according to claim 16, further comprising converting the compound of Formula (Π-0) into the compound of Formula (I).

18. The process according to any one of claims 13-17, wherein R^PA is a Boc group.

19. The process according to any one of claims 13-17, wherein R^p is a trityl group.

20. The process according to any one of claims 13-19, wherein R^x is H. 21. The process according to any one of claims 13-19, wherein R^x is R^PH.

22. The process according to claim 21, wherein R^PH is a fert-butyl group.

23. A process for preparing a compound of Formula (IV -H):

comprising the steps of:

1) treating a compound

with a compound having Formula (Π-Β):

wherein R^PA is an amine protecting group and R^x is H or R^PH, wherein h> droxyl protecting group, to fonn a compound of Formula (II-CH):

OR^x

NHR^PA

OH (II-CH),

wherein R^p is an amine protecting group;

cyclizing the compound of Formula (II-EH) to form the compound of Formula

5) converting the compound of Formula (III-H) into the compound of Formula (IV-

24. The process according to claim 23, wherein R^PA is a Boc group.

25. The process according to claim 23 or claim 24, wherein R^p is a trityl group.

26. The process according to any one of claims 23-25, wherein R^x is H.

27. The process according to any one of claims 23-25, wherein R^x is R^PH.

28. The process according to claim 27, wherein R^PH is a fert-butyl group.

29. A process for preparing a compound of Formula (IV-H):

comprising the steps of: 1) treating a compound having Formula (II -KH):

with a compound having Formula (Π-Β):

wherein R^p is an amine protecting group, and

5) cyclizing the compound of Formula (II-OH) to form the compound of Formula (III-H):

6) converting the compound of Formula (III-H) into the compound of Formula (IV- H).

30. The process according to claim 29, wherein R^PA is a Boc group.

31. The process according to claim 29 or claim 30, wherein R^p is a trityl group.

32. The process according to any one of claims 29-31, wherein R^x is H.

33. The process according to any one of claims 29-31, wherein R^x is R¹

The process according to claim 33, wherein R^PH is a fert-butyl group.

A process for preparing a compound having the formula:

comprising the steps of:

NHBoc

I Oo

to form a compound havi

2) converting the compound formed in step 1) to a compound having the formula:

3) converting the compound formed in step 2) to a compound having the formula:

converting the compoun mpound having the formula:

converting the compound formed in step 4) to a compound having the formula:

treating the compound formed in step 5) with a compound having the formula:

to form said compound.

A process for preparing a compound having the formula:

comprising the steps of:

to form a compound having the formula:

2) converting the compound formed in step 1) to a compound having the formula:

3) converting the compound formed in step 2) to a compound having the formula:

4) converting the compoun mpound having the formula:

converting the compoun mpound having the formula:

6) converting the compoun mpound having the formula:

7) treating the compound formed in step 6) with a compound having the formula:

to form said compound.

37. A compound which is:

(,S)-fert-butyl (3-hydroxy-l-((2-hydroxyphenyl)(methyl)amino)-l -oxopropan-2 - yl)carbamate,

(<S)-benzyl (3-hydroxy- 1 -((2-hydroxyphenyl)(methyl)amino)- 1 -oxopropan-2 - yl)carbamate, (<S)-fert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [l,4]oxazepin-3-yl)carbamate, (<S)-fert-butyl (3-(i-butoxy)-l-((2-hydroxyphenyl)(methyl)amino)- l-oxopropan-2- yl)carbamate,

(5)-3-hydroxy-N-(2-hydroxyphenyl)-N-methyl-2-(tritylamino) propanamide,

(5)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)-one,

(5)-3-hydroxy-N-(2-hydroxyphenyl)-N-methyl-2-(tritylamino) propanamide,

(5)-2-amino-N-(2-fluorophenyl)-3-hydroxy-N-methylpropanamide,

(¾-N-(2-fluorophenyl)-3-hydroxy-N-methyl-2-(tritylamino)propanamide,

(5)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)-one,

(5)-3-amino-5-methyl-2,3-dihydrobenzo[b] [l,4]oxazepin-4(5H)-one ,

or a salt thereof.