WO2018205948A1

WO2018205948A1 - Compounds

Info

Publication number: WO2018205948A1
Application number: PCT/CN2018/086131
Authority: WO
Inventors: Xin HAO; Xin Ma; Feng Ren; Zehong Wan
Original assignee: GlaxoSmithKline China R&D Co Ltd; GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline China R&D Co Ltd; GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2017-05-11
Filing date: 2018-05-09
Publication date: 2018-11-15
Anticipated expiration: 2019-11-11
Also published as: AR112187A1; UY37729A; TW201908310A

Abstract

Provided are benzoxazolinone sulfonamide derivatives that inhibit Na _v1.7 activity, pharmaceutical compositions containing them and their use in therapy for the treatment of diseases mediated by Na _v1.7 activity.

Description

COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to novel compounds that inhibit Na _v1.7 activity, pharmaceutical compositions containing them and their use in therapy for the treatment of diseases mediated by Na _v1.7 activity.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSCs or Na _v) are integral membrane proteins that play an essential role in regulating electrical signaling in excitable cells such as neurons. Nine VGSC subtypes (Na _v1.1 -Na _v1.9) have been identified in mammals (Goldin et al., Neuron 28, 365-68 (2000) ) . These subtypes exhibit tissue specific expression, for example, Na _v1.2, and Na _v1.3 are expressed in the central nervous system (CNS) ; Na _v1.5 is expressed in heart, and Na _v1.7, Na _v1.8, and Na _v1.9 are expressed primarily in the peripheral nervous system (PNS) (Goldin et al., Ann. N.Y.Acad. Sci. 868, 38-50 (1999) . The 9 subtypes can be functionally divided into two groups -those are sensitive to blocking by tetrodotoxin (TTX-sensitive) which are Na _v1.1, Na _v1.2, Na _v1.3, Na _v1.4, Na _v1.6 and Na _v1.7; and those are resistant to blocking by tetrodotoxin (TTX-resistant) which are Na _v1.5, Na _v1.8, and Na _v1.9.

VGSCs are composed of one α-subunit and several auxiliary β-subunits. The α-subunit of Na _v1.7 is encoded by the SCN9A gene which is preferentially expressed in peripheral sympathetic and sensory neurons (Toledo-Aral et al., Proc. NatlAcad. Sci. USA 94, 1527-1532 (1997) ) . The critical role for Na _v1.7 in pain signaling has been shown by mutations in the SCN9A gene in humans including inherited erythromelalgia (IEM) (Dib-Hajj et al., Ann. Rev. Neurosci. 33, 325 (2010) ) , paroxysmal extreme pain disorder (PEPD) (Fertleman, et al., Neuron 52, 767-774 (2006) ) , primary erythermalgia (PE) (Yang et al., J. Med. Genet. 41, 171-174 (2004) ) , small fiber neuralgia (SFN) , and congenital insensitivity to pain (CIP) (Bennett et al., Lancet Neurol. 13, 587-599 (2014) ) . Studies of patients with IEM, PEPD and SFN revealed gain-of-function SCN9A mutations resulting in hyperexcitability of dorsal root ganglia (DRG) neurons (Cheng et al., Mol. Pain 6, 24 (2010) ) , whereas loss-of-function SCN9A mutations were linked to the inability of CIP patients to experience pain (Cox et al., Nature 444, 894-898 (2006) ) .

Na _v1.7 has been implicated in various pain disorders such as acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, cancer pain, back and orofacial pain, osteoarthritis, dental pain, diabetic peripheral neuropathy, postherpetic neuralgia. (Nassar et al., Proc. Natl. Acad. Sci. 101, 12706-12711 (2004) ; Cummins et al., J. Neurosci. 24, 8232-8236 (2004) ; Reimann, et. al., Proc. Natl. Acad. Sci. 107, 5148-5153 (2010) ; international applications WO2014066490 and WO2013063459) .

In light of the role Na _v1.7 plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate Na _v1.7 activity, which can be used in the treatment of diseases mediated by Na _v1.7.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to compounds of Formula (I) and salts (e.g., pharmaceutically acceptable salts) thereof,

wherein

-R1 is selected from the group consisting of:

i) cyclopropyl substituted with piperidinyl or C _1-3alkyl;

wherein:

the C _1-3alkyl is substituted with piperidinyl or NH ₂;

ii) phenyl substituted with (CH ₂) _mNRxRy;

wherein:

m is 1 or 2, Rx is H or methyl;

Ry is H, methyl, CH ₂CH ₂OH, CH ₂COOH or CH ₂CH ₂NH ₂;

iii) phenyl substituted with methyl;

wherein:

the methyl is substituted with one to three substituents independently selected from the group consisting of OH, halo, CH ₂NH ₂ and morpholinyl;

iv) phenyl substituted with 4 to 6 membered heterocycloalkyl;

wherein:

the heterocycloalkyl is optionally substituted with one substituent selected from the group consisting of methyl, halo and methoxy;

v) phenyl substituted with two substituents independently selected from the group consisting of halo and C _1-3alkyl;

wherein:

the C _1-3alkyl is optionally substituted with one substituent selected from the group consisting of NH ₂, N (CH ₃) ₂ and NHCH ₂ (C=O) NH ₂;

vi) phenyl substituted with tetrahydropyridinyl;

wherein:

the tetrahydropyridinyl is optionally substituted with methyl;

vii) tetrahydroisoquinolinyl;

wherein:

the tetrahydroisoquinolinyl is optionally substituted with methyl;

viii) tetrahydronaphthalenyl;

wherein:

the tetrahydronaphthalenyl; is optionally substituted with NH ₂ or OH;

-R2 is H or halo and R3 is H or halo;

wherein:

one of R2 and R3 is H and the other is halo;

-R4 is methyl or H; and

-Het is 5 or 6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, S and O; and

wherein:

the heteroaryl is optionally substituted with one substituent selected from halogen, C _1-3alkyl and CN.

In a further aspect of the invention, the invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

A further aspect of the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of disorders described herein.

DETAILED DESCRIPTION OF THE INVENTION

As used in the description of the embodiments of the invention and the appended claims, the singular forms “a” , “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, “and/or” refers to encompasses any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms “comprises” and/or “comprising” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there is a plurality of definitions for a term used herein, those in this section prevail unless stated otherwise.

A. Definitions

As used herein, unless otherwise indicated, “alkyl” is a monovalent, saturated hydrocarbon chain having a specified number of carbon atoms. C _1-3alkyl refers to an alkyl group having from 1 to 3 carbon atoms. Alkyl groups may be straight or branched. In some embodiments, branched alkyl groups may have one or two branches. Exemplary alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl) .

As used herein, unless otherwise indicated, “halogen” refers to fluorine (F) , chlorine (Cl) , bromine (Br) , or iodine (I) . Halo refers to the halogen radicals: fluoro (-F) , chloro (-Cl) , bromo (-Br) , or iodo (-I) .

As used herein, unless otherwise indicated, “heteroaryl” is a monovalent radical derived by removal of a hydrogen atom from a monocyclic 5 or 6 membered heteroaromatic ring, which ring consists of ring-carbon atoms and ring-heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, and which ring is aromatic. In one embodiment, the “5 or 6 membered heteroaryl” is a monocyclic 5 membered heteroaromatic ring and contains one, two or three heteroatom ring members independently selected from the group consisting of N, S and O. Exemplary heteroaryls include, but are not limited to, thiazolyl, pyridinyl, thiadiazolyl and isoxazolyl.

“Heterocycloalkyl” refers to a non-aromatic saturated monocyclic ring containing 4 to 6 ring atoms one of which is a N atom and the rest are carbon atoms. Examples ofheterocycloalkyls include pyrrolidinyl, piperidinyl and azetidinyl.

As used herein, unless otherwise indicated, “optionally substituted” indicates that a group or a ring may be unsubstituted, or the group or a ring may be substituted with one to three substituent as defined herein.

As used herein, unless otherwise indicated, “substituted” in reference to a group indicates that one or more hydrogen atom attached to a member atom (e.g., carbon atom) within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture) . When it is stated that a group may contain one or more substituent, one or more (as appropriate) member atom within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

As used herein, unless otherwise indicated, “disorder” refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disorder can also include a distemper, ailing, ailment, malady, sickness, illness, complain, interdisposition and/or affectation.

As used herein, unless otherwise indicated, “treat” , “treating” or “treatment” in reference to a disorder means: (1) to ameliorate the disorder or one or more of the biological manifestations of the disorder, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the disorder or (b) one or more of the biological manifestations of the disorder, (3) to alleviate one or more of the symptoms or effects associated with the disorder, (4) to slow the progression of the disorder or one or more of the biological manifestations of the disorder, and/or (5) to diminish the likelihood of severity of a disorder or biological manifestations of the disorder.

As used herein, unless otherwise indicated, “subject” means a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc. ) , and particularly human subjects including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects, and further including various races and ethnicities including, but not limited to, white, black, Asian, American Indian and Hispanic.

As used herein, unless otherwise indicated, “pharmaceutically acceptable” refers to those compounds (including salts) , materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, unless otherwise indicated, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in treating a disorder, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A therapeutically effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound) ; the route of administration chosen; the disorder being treated; the severity of the disorder being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

B. Compounds

wherein

-R1 is selected from the group consisting of:

i) cyclopropyl substituted with piperidinyl or C _1-3alkyl;

wherein:

the C _1-3alkyl is substituted with piperidinyl or NH ₂;

ii) phenyl substituted with (CH ₂) _mNRxRy;

wherein:

m is 1 or 2, Rx is H or methyl;

Ry is H, methyl, CH ₂CH ₂OH, CH ₂COOH or CH ₂CH ₂NH ₂;

iii) phenyl substituted with methyl;

wherein:

iv) phenyl substituted with 4 to 6 membered heterocycloalkyl;

wherein:

vi) phenyl substituted with tetrahydropyridinyl;

wherein:

the tetrahydropyridinyl is optionally substituted with methyl;

vii) tetrahydroisoquinolinyl;

wherein:

the tetrahydroisoquinolinyl is optionally substituted with methyl;

viii) tetrahydronaphthalenyl;

wherein:

the tetrahydronaphthalenyl; is optionally substituted with NH ₂ or OH;

-R2 is H or halo and R3 is H or halo;

wherein:

one of R2 and R3 is H and the other is halo;

-R4 is methyl or H; and

wherein:

In one embodiment, R1 is cyclopropyl substituted with piperidinyl. In one embodiment, R1 is C _1-3alkyl substituted with piperidinyl or NH ₂. In one embodiment, R1 is methyl substituted with piperidinyl. In one embodiment, R1 is ethyl substituted with NH ₂. In one embodiment, R1 is propyl substituted with NH ₂.

In one embodiment, R1 is phenyl substituted with aminomethyl. In one embodiment, R1 is phenyl substituted with aminoethyl. In one embodiment, R1 is phenyl substituted with (dimethylamino) methyl. In one embodiment, R1 is phenyl substituted with methyl which is substituted with NHCH ₂CH ₂OH. In one embodiment, R1 is phenyl substituted with methyl which is substituted with NHCH ₂COOH. In one embodiment, R1 is phenyl substituted with methyl substituted with NHCH ₂CH ₂NH ₂.

In one embodiment, R1 is phenyl substituted with with methyl which is substituted with one to three substituents independently selected from the group consisting of OH, halo, CH ₂NH ₂ and morpholinyl. In one embodiment, R1 is phenyl substituted with hydroxymethyl. In one embodiment, R1 is phenyl substituted with morpholinomethyl. In one embodiment, R1 is phenyl substituted with methyl which is substituted with two F and one CH ₂NH ₂.

In one embodiment, R1 is phenyl substituted with 4 to 6 membered heterocycloalkyl, said heterocycloalkyl is optionally substituted with one substituent selected from the group consisting of methyl, halo and methoxy. In one embodiment, R1 is phenyl substituted with piperidinyl optionally substituted with methyl. In one embodiment, R1 is phenyl substituted with pyrrolidinyl. In one embodiment, R1 is phenyl substituted with azetidinyl substituted with F. In one embodiment, R1 is phenyl substituted with azetidinyl substituted with methoxy.

In one embodiment, R1 is phenyl substituted with two substituents independently selected from the group consisting of methyl, halo, and C _1-3alkyl optionally substituted with NH ₂, N (CH ₃) ₂ or NHCH ₂ (C=O) NH ₂. In one embodiment, R1 is phenyl substituted with F and aminoethyl. In one embodiment, R1 is phenyl substituted with methyl and aminomethyl. In one embodiment, Ri is phenyl substituted with methyl and (dimethylamino) methyl. In one embodiment, R1 is phenyl substituted with 1) methyl and 2) methyl substituted with NHCH ₂ (C=O) NH ₂.

In one embodiment, R1 is phenyl substituted with tetrahydropyridinyl. In one embodiment, R1 is phenyl substituted with tetrahydropyridinyl, said tetrahydropyridinyl is substituted with methyl.

In one embodiment, R1 is tetrahydroisoquinolinyl. In one embodiment, R1 is tetrahydroisoquinolinyl substituted with methyl. In one embodiment, R1 is tetrahydronaphthalenyl. In one embodiment, R1 is tetrahydronaphthalenyl substituted with NH ₂. In one embodiment, R1 is tetrahydronaphthalenyl substituted with OH.

In one embodiment, one of R2 and R3 is H, the other is halogen. In one embodiment, R2 is H and R3 is F. In one embodiment, R2 is F and R3 is H.

In one embodiment, Het is 5 or 6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, S and O. In one embodiment, Het is 5 or 6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, S and O, said heteroaryl is substituted with one substituent selected from halogen, C _1-3alkyl and CN. In one embodiment, Het is thiazolyl. In one embodiment, Het is thiazol-4-yl. In one embodiment, Het is thiazolyl substituted with methyl. In one embodiment, Het is thiazolyl substituted with CN. In one embodiment, Het is pyridinyl. In one embodiment, Het is pyridinyl substituted with F. In one embodiment, Het is isoxazoly. In one embodiment, Het is thiadiazolyl.

In one embodiment, the compound of Formula (I) is a compound of any one of Examples 1 to 101, a free base or a salt (e.g., a pharmaceutically acceptable salt) thereof.

In one embodiment, the compound of Formula (I) is a compound of any one of below compounds:

7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (aminomethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (aminomethyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- (1- (2- (pyrrolidin-3-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (2-amino-1, 1-difluoroethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (2-amino-1, 1-difluoroethyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (1- (3-aminopropyl) cyclopropyl) methyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-2-oxo-3- (1- (1- (piperidin-4-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- (1- (1- (piperidin-4-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-2-oxo-3- (1- (1- (piperidin-3-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- (1- (1- (piperidin-3-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- ( (1- (piperidin-2-yl) cyclopropyl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- (1- (1- (piperidin-2-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (1- (3-aminopropyl) cyclopropyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (2-aminoethyl) -3-fluorophenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamide,

4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (5-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (6-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- (1- (1- (piperidin-3-ylmethyl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (2- (aminomethyl) -3-methylbenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

2- ( (2- ( (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) methyl) -6-methylbenzyl) amino) acetamide,

7-fluoro-2-oxo-3- ( (1- (piperidin-4-ylmethyl) cyclopropyl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (1- (2-aminoethyl) cyclopropyl) methyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (1- (2-aminoethyl) cyclopropyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (2-aminoethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) methyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- ( (dimethylamino) methyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- ( (dimethylamino) methyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (aminomethyl) -3-methylphenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (aminomethyl) -3-methylphenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- (1- (1- (piperidin-4-ylmethyl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-N- (6-fluoropyridin-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-N- (6-fluoropyridin-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (R) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -4-fluoro-2-oxo -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (S) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- ( (S/R) -7-amino -5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -4-fluoro-2-oxo -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (R) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- ( (S) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- ( (S/R) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -7-fluoro-2-oxo-N- (thiazo l-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro -3- (1- (2- (3-methoxyazetidin-3-yl) phenyl) ethyl) -2-oxo -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-3- (1- (2- (3-methoxyazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (azetidin-3-yl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (azetidin-3-yl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (azetidin-1-yl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- (azetidin-1-yl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (6-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (isoxazol-3-yl) -2-oxo -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide.

(R) -4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide.

(S) -4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide.

(R) -7-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-2-oxo-3- ( (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide.

7-fluoro-2-oxo-3- ( (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide.

3- (2- ( (dimethylamino) methyl) -3-methylbenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide.

2- ( (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) benzyl) amino) acetic acid,

2- ( (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) benzyl) amino) acetic acid,

4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (4-methylthiazol-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

N- (4-cyanothiazol-2-yl) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

7-fluoro-2-oxo-3- ( (1- (piperidin-3-ylmethyl) cyclopropyl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-3- (1- (isoindolin-4-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-3- (1- (isoindolin-4-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

3- (1- (2- ( ( (2-aminoethyl) amino) methyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 3, 4-thiadiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-N- (4-methylthiazol-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 3, 4-thiadiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamid,

(S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-N- (4-methylthiazol-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

rac-4-fluoro-3- ( (R) -1- ( (R) -7-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

rac-4-fluoro-3- ( (R) -1- ( (S) -7-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-3- (1- (2- (morpholinomethyl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

4-fluoro-3- (1- (2- ( ( (2-hydroxyethyl) amino) methyl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamide,

(R) -4-fluoro-3- (1- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-3- (1- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(S) -7-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -4-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (1, 2, 4-thiadiazol-5-y, ) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-3- (1- (2- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-3- (1- (2- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2-oxo-N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

(R) -7-fluoro-3- (1- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

or racemate thereof or salts (e.g. pharmaceutically acceptable salts) thereof.

In one embodiment, the compound of Formula (I) is (R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is (R) -7-fluoro-3- (1- (2- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are selective for the Na _v1.7 channel over Na _v1.5. In particular, they show an affinity for the Na _v1.7 channel which is greater than their affinity for Na _v1.5 channel, and selectively block Na _v1.7 activity. Certain compounds of the present invention may have improved physicochemical properties.

The compounds of the above referenced formulas or salts (e.g., pharmaceutically acceptable salts) thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms) . The different isomeric forms may be separated or resolved one from the other by conventional methods (e.g. chiral HPLC) , or any given isomer may be obtained by conventional synthetic methods e.g. stereospecific or asymmetric syntheses. In some cases, the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The compounds of the above referenced formulas or salts (e.g., pharmaceutically acceptable salts) thereof may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

"Enantiomers" refer to asymmetric molecules that can exist in two different isomeric forms which have different configurations in space. The designations, "R" and "S" , for the absolute configuration of an enantiomer of the invention may appear as a prefix or as a suffix in the name of the compound. "Enantiomeric excess" or "ee" as used herein refers to when one enantiomer is present in excess of the other, and is defined as the absolute difference in the mole fraction of each enantiomer. Enantiomeric excess is typically expressed as a percentage of an enantiomer present in a mixture relative to the other enantiomer. In one embodiment, the enantiomers of the present invention have ee greater than 80%. In one embodiment, the enantiomers of the present invention have ee greater than 90%. In one embodiment, the enantiomers of the present invention have ee greater than 95%. In one embodiment, the enantiomers of the present invention have ee greater than 99%.

The invention also includes various deuterated forms of compounds of the above referenced formulas, salts (e.g., pharmaceutically acceptable salts) thereof. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of compounds of the above referenced formulas, salts (e.g., pharmaceutically acceptable salts) thereof. Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of compounds of the above referenced formulas, salts (e.g., pharmaceutically acceptable salts) thereof, or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride) .

It is to be understood that the references herein to a compound of Formula (I) or a salt thereof includes a compound of Formula (I) as a free base, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of Formula (I) . In another embodiment, the invention is directed to a salt of a compound of Formula (I) . In a further embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of Formula (I) . In another embodiment, the invention is directed to a compound of Formula (I) or a salt thereof. In a further embodiment, the invention is directed to a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Compounds of Formula (I) have both a basic amine group and a carboxylic acid group and can consequently be in the form of a zwitterion, also known as an inner salt. Therefore, in an embodiment the compound of Formula (I) is in a zwitterion form.

Because of its potential use in medicine, it will be appreciated that a salt of a compound of Formula (I) is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley-VCH/VHCA, 2011 (see http: //www. wiley. com/WileyCDA/WileyTitle/productCd-3906390519. html) .

Non-pharmaceutically acceptable salts are within the scope of the present invention, for example for use as intermediates in the preparation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Non-pharmaceutically acceptable salts may be used, for example as intermediates in the preparation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts can include acid or base addition salts.

Such base addition salts can be formed by reaction of a compound of Formula (I) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration. Such acid addition salts can be formed by reaction of a compound of Formula (I) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I) . If a basic compound of Formula (I) 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. Similarly, if a compound of Formula (I) 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.

It will be understood that if a compound of Formula (I) contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt. Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of formula (I) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.

The compounds of the above referenced formulas and salts (including pharmaceutically acceptable salts) thereof may be in the form of a solvate. For solvates of the compounds of the above referenced formulas, including solvates of salts of the compounds of the above referenced formulas, that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as “hydrates. ” Solvates include stoichiometric solvates as well as compositions containing variable amounts of the incorporated solvent (s) , e.g. a hydrate includes stoichiometic hydrates and compositions containing variable amounts of water.

The compounds described herein, their salts (e.g., pharmaceutically acceptable salts) , deuterated form, solvates or hydrates thereof, may exist in one or more polymorphic form. Therefore, in a further aspect, the invention provides a polymorph of a compound defined herein, their salts (e.g., pharmaceutically acceptable salts) , or a polymorph of a solvate or hydrate of a compound described herein or a salt (e.g., pharmaceutically acceptable salt) thereof.

The invention also includes isotopically labeled compounds and salts, which are identical to compounds of the above referenced formulas or salts thereof, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the above referenced formulas or salts thereof isotopes of hydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C and ¹⁸F. Such isotopically-labeled compound of the above referenced formulas or salts thereof are useful in drug and/or substrate tissue distribution assays. For example, ¹¹C and ¹⁸F isotopes are useful in PET (positron emission tomography) . PET is useful in brain imaging. Isotopically-labeled compounds of the above referenced formulas and salts thereof can generally be prepared by carrying out the procedures disclosed below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent. In one embodiment, compounds of the above referenced formulas or salts thereof are not isotopically labeled.

As used herein, the terms “compound (s) of the invention” or “compound (s) of the present invention” mean a compound of the above referenced formulas, as defined herein, in any form, i.e., any salt or non-salt form (e.g., as a free base form, or as a salt, for example, a pharmaceutically acceptable salt thereof) , deuterated form and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms) , and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di-and hemi-hydrates) ) , and mixtures of various forms. In the context of pharmaceutical compositions and methods of treatment discussed herein, the terms of “compounds of the invention” mean a compound of the above referenced formulas, as defined herein, in the form of any pharmaceutically acceptable salt thereof or non-salt form (e.g., as a free acid or base form) , deuterated form and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms) , and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di-and hemi-hydrates) ) , and mixtures of various forms.

Accordingly, a compound of the invention includes a compound of the above referenced formulas, or a salt thereof, for example a pharmaceutically acceptable salt thereof. Representative compounds of this invention include the specific compounds described.

C. Synthesis of Compounds

The process to be utilized in the preparation of the compounds described herein depends upon the desired compounds. Such factors as the selection of the specific substituent and various possible locations of the specific substituent all play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.

In general, the compounds of the present invention may be prepared by standard techniques known in the art and by known processes analogous thereto. General methods for preparing compounds of formula (I) are set forth below. All starting material and reagents described in the below general experimental schemes are commercially available or can be prepared by methods known to one skilled in the art.

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed. ) , John Wiley &Sons, NY (1999) . In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

Scheme 1

[Exemplary conditions: a) CDI, DCM, ACN; b) CISO ₃H, -20℃ to RT to 70℃; c) NBS, ACN; d) BnSH, Xantphos, Pd ₂ (dba) ₃, DIPEA, 1, 4-dioxane, 100℃

Scheme 1 represents a general reaction scheme for preparing intermediates 1.3 &1.5. Compounds 1.1 can be obtained commercially. Compound 1.2 can be obtained by reacting compound 1.1 with 1, 1′-carbonyldiimidazole in a suitable solvent such as dichloromethane and acetonitrile. Compound 1.3 can be obtained by treating compound 1.2 with chlorosulfonic acid at a suitable temperature from -20℃ to RT to 70℃. Compound 1.4 can be obtained by reacting compound 1.2 with N-bromosuccinimide in acetonitrile, followed by coupling reaction with BnSH using a suitable catalyst such as Pd ₂ (dba) ₃, a suitable ligand such as Xantphos and a suitable base such as N, N-diisopropylethylamine in a suitable solvent such as 1, 4-dioxane, at suitable temperature such as 100℃.

Scheme 2

[Exemplary conditions: a) LiHMDS, THF, -78 ℃ to RT; b) Ph ₃P, DEAD or DIAD, THF, 0℃ to RT; c) NCS, AcOH/H ₂O, 0℃ to RT; 1, 3-dichloro-5, 5-dimethyl-imidazoline-2, 4-dione, ACN/AcOH/H ₂O, -10℃; d) K ₂CO ₃, 1, 4-dioxane/H ₂O or 1, 4-dioxane, RT to 80℃; e) pyridine, DMAP, DCM, RT; f) CMBP, toluene, 80℃; g) TFA, DCM, 0℃ or RT; or HCl, MeOH or EA or Et ₂O, 0℃ or RT;

Scheme 2 represents a general reaction scheme for preparing certain intermediates and compounds of Formula (I) . Compounds 2.1, 2.3, and 2.6 can be obtained commercially or be made from commercially available starting materials using methods known to those skilled in the art. Intermediate 2.2 can be obtained by treating Intermediate 1.3 with a protected amine 2.1 using a suitable base such as LiHMDS in suitable solvent such as THF at a suitable temperature depending on the choice of base, for example, from -78℃ to RT. Intermediate 2.4 can be obtained by a Mitsunobu reaction of 1.5 and 2.3 using a suitable phosphines reagent such as triphenylphosphine, and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) , in a suitable solvent such as THF, at suitable temperature such as from 0℃ to RT. Intermediate 2.5 can be obtained by treating 2.4 with a suitable oxidation reagent such as 1, 3-dichloro-5, 5-dimethyl-imidazoline-2, 4-dione or N-chlorosuccinimide (NCS) , in a suitable solvent such as acetonitrile and acetic acid and water, or acetic acid and water only, at a suitable temperature such as RT. Intermediate 2.7 can be obtained by a Mitsunobu reaction of 2.2 and 2.3 using a suitable phosphines reagent such as triphenylphosphine, and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) , at suitable temperature such as 0℃ to RT; or by a reaction of 2.2 and 2.3 using a suitable phosphines reagent such as (cyanomethylene) tributylphosphorane (CMBP) , in a suitable solvent such as toluene, at suitable temperature such as 80℃. Alternatively, 2.7 could be obtained by nucleophilic substitution reaction of 2.2 and 2.6 using a suitable base such as K ₂CO ₃, in a suitable solvent such as 1, 4-dioxane and water, or 1, 4-dioxane only, at a suitable temperature such as from RT to 80℃. Intermediate 2.7 can also be obtained by the reaction of compound 2.5 and compound 2.1 with suitable bases such as pyridine and 4-dimethylaminopyridine (DMAP) , in suitable solvent such as dichloromethane, at a suitable temperature such as RT. In step g, certain compounds of Formula (I) can be obtained by deprotection of 2.7 with a suitable acid in a suitable solvent such as TFA in DCM, or HCl in MeOH or Et ₂O or EA.

Scheme 3

[Exemplary conditions: a) Ph ₃P, DIAD, THF, 0℃ to RT; d) TFA, DCM, 0℃ or RT; or HCl, MeOH or EA or Et ₂O;

Scheme 3 represents a general reaction scheme for preparing certain intermediates and compounds of Formula (I) . Compound 3.1 can be obtained commercially or be made from commercially available starting materials using methods known to those skilled in the art. Intermediate 3.2 can be obtained by a Mitsunobu reaction of 2.2 and 3.1 using a suitable phosphines reagent such as triphenylphosphine, and an azodicarboxylate such as diisopropyl azodicarboxylate (DIAD) in a suitable solvent such as THF at a suitable temperature such as from 0℃ to RT. In step b, certain compounds of Formula (I) can be obtained by deprotection of 3.2 with a suitable acid in a suitable solvent such as TFA in DCM, or HCl in MeOH or Et ₂O or EA.

Scheme 4

[Exemplary conditions: a) TEA, DCM, 0℃ to RT; b) Ph ₃P, DEAD or DIAD, THF, 0℃ to RT;

c) tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate, K ₂CO ₃, PdCl ₂ (dppf) -CH ₂Cl ₂ adduct, 1, 4-dioxane, mw, 100℃ d) H ₂, Pd/C (10%w/w) , EtOH, EA, RT

Scheme 4 represents a general reaction scheme for preparing certain intermediates of compounds of Formula (I) . Compounds 4.1, 4.3 and 4.5 can be obtained commercially or be made from commercially available starting materials using methods known to those skilled in the art. Intermediate 4.2 can be obtained by treating intermediate 1.3 with a protected amine 4.1 using suitable base such as triethylamine (TEA) in a suitable solvent such as dichloromethane, at a suitable temperature such as RT. Intermediate 4.4 (a) can be obtained by a Mitsunobu reaction of 4.2 and 4.3 using a suitable phosphines reagent such as triphenylphosphine, and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in a suitable solvent such as THF at a suitable temperature such as from 0℃ to RT. Similarly, intermediate 4.6, where R ₁ is 2-bromophenyl, can be obtain by a Mitsunobu reaction of 4.2 and compound 4.5 where R ₁ is 2-bromophenyl, using a suitable phosphines reagent such as triphenylphosphine, and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in a suitable solvent such as THF at a suitable temperature such as from 0℃ to RT. Intermediate 4.4 (b) , where R ₁ is 2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl, can be obtained by a Suzuki cross coupling reaction of 4.6 and tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate with a suitable catalyst such as PdCl ₂ (dppf) -CH ₂Cl ₂ adduct, a suitable base such as K ₂CO ₃, in a suitable solvent such as 1, 4-dioxane at suitable temperature such as 100℃ by a suitable heating method such as microwave. Intermediate 4.4 (c) , where R ₁ is 2- (piperidin-4-yl) phenyl, can be obtained by a hydrogenation reaction of 4.4 (b) with hydrogen by a suitable catalyst such as Palladium on carbon in a suitable solvent such as ethanol and ethyl acetate, at a suitable temperature such as RT.

Scheme 5

[Exemplary conditions: a) TFA, DCM, 0℃ or RT; b) Boc ₂O, TEA or NaHCO ₃, DCM, RT; c) NH ₃H ₂O, H ₂O/ACN, 0℃ to RT; d) Cul, Cs ₂CO ₃ or K ₂CO, N ¹, N ²-dimethylcyclohexane-1, 2-diamine, ACN, 67℃ to 100℃; e) TFA, DCM, 0℃ or RT; or HCl, MeOH or EA or Et ₂O, 0℃ or RT f) formaldehyde, NaBH (OAc) ₃, DCM, RT

Scheme 5 represents a general reaction scheme for preparing certain intermediates and compounds of Formula (I) . Compound 5.2 can be obtained commercially or be made from commercially available starting materials using methods known to those skilled in the art. Intermediate 5.1 can be obtained by treating 4.4 (a) , 4.4 (b) or 4.4 (c) with a suitable acid such as TFA in a suitable solvent such as DCM at a suitable temperature such as 0℃ or RT, followed by treatment of di-tert-butyl dicarbonate with a suitable base such as NaHCO ₃ or triethylamine in a suitable solvent such as dichloromethane at a suitable temperature such as RT. Alternatively, 5.1 can be obtained by treating 2.5 with NH ₃H ₂O in a suitable solvent such as acetonitrile and water, at a suitable temperature such as 0℃ or RT. Intermediate 5.3 can be obtained by coupling reaction of 5.1 with 5.2 with a suitable catalyst such as CuI, a suitable bas such as Cs ₂CO ₃ or K ₂CO ₃ and a suitable ligand such as N ¹, N ²-dimethylcyclohexane-1, 2-diamine, in a suitable solvent such as THF at a suitable temperature which may vary from 67℃ to 100℃. In step e, certain compounds of Formula (I) can be obtained by deprotection of intermediate 5.3 with a suitable acid in a suitable solvent such as TFA in DCM, or HCl in MeOH or Et ₂O or EA. In step f, compounds of Formula (I) , where R ₁ 2- (1-methylpiperidin-4-yl) phenyl, 2- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl, 2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl or 2- ( (dimethylamino) methyl) -3-methylphenyl, can be obtained by a further reductive amination reaction of compounds of Formula (I) obtained from step e where R ₁ is 2- (piperidin-4-yl) phenyl, 2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl, 1, 2, 3, 4-tetrahydroisoquinolin-8-yl or 2- (aminomethyl) -3-methylphenyl, with formaldehyde and a reductive reagent such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane at a suitable temperature such as RT.

Examples

The following synthetic processes and examples are provided to more specifically illustrate the invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the invention. While particular embodiments of the 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.

The chemical names of compounds described in the present application follows the principle of IUPAC nomenclature.

Heating of reaction mixtures with microwave irradiations was carried out in an Biotage Initiator (purchased from Biotage Sweden AB) .

Conventional techniques may be used herein for work up of reactions and purification of the products of the Examples. Purification of the compounds in the examples may be carried out by conventional methods such as chromatography and/or re-crystallization using suitable solvents. Chromatographic methods are known to the skilled person and include e.g. column chromatography, flash chromatography, HPLC (high performance liquid chromatography) , chiral HPLC and MDAP (mass directed auto-preparation, also referred to as mass directed LCMS purification) . MDAP is described in e.g. W. Goetzinger et al, Int. J. Mass Spectrom., 2004, 238, 153-162. Unless otherwise stated, flash column chromatography was performed on silica gel.

Analtech Silica Gel GF-254 thin layer plates and Sanpont GF-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on SanPont silica gel (100-200, 200-300 or 300-400 mesh) . The Compact Purifier system used for purification in this application was purchased from LISURE (SuZhou) Inc. The CombiFlash system used for purification in this application was purchased from Companion. The Compact Purifier purification and CombiFlash purification was carried out using a pre-packed silica gel column, a detector with UV wavelength at 254 nm or 214 nm and mixed solvents (petroleum ether and ethyl acetate) .

Final compounds were characterized with LCMS (conditions listed below) and NMR. ¹H NMR or ¹⁹FNMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer, Bruker Avance 400 MHz spectrometer and Varian Mercury Plus-300 MHz spectrometer. CDCl ₃ is deuteriochloroform, DMSO-d ₆ is hexadeuteriodimethylsulfoxide, and CD ₃OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS) or the NMR solvent. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz.

In the procedures that follow, after each starting material, reference to an intermediate is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Absolute stereochemistry can be determined by methods known to one skilled in the art, for example X-ray or Vibrational circular dichroism (VCD) .

In the Descriptions or Examples described herein, the use of a solid full bond and a dashed full bond

means the substituents are in a trans-configuration with respect to the plane of the ring that the substituents are attached to. Where the absolute stereochemistry is known and the compound is a single enantiomer, the bold and/or hashed wedge symbol

are used.

LCMS Conditions:

Instruments:

HPLC: Waters UPLC H-class, Agilent 1200; 1260 and

MS: Agilent 1956A; 6110; 6120

1) Acidic conditions:

Mobile phase: Water containing 0.1%TFA /ACN

Column: waters acquity UPLC BEH C18 1.7 μm, 2.1×50 mm

Detection: MS: waters acquity UPLC SQ Detector and

LC: waters acquity UPLC PDA eλ Detector

2) Acidic conditions:

Mobile phase: Water containing 0.01%TFA /ACN containing 0.01%TFA

Column: Chromolith Fast Gradien RP-18e, 50-3 mm

Detection: MS and photodiode array (PDA) detector

3) Acidic conditions:

Mobile phase: Water containing 0.05 %TFA /ACN

Column: Agilent SB-C18 4.6 x 30 mm-1.8 microns

Detection: MS and photodiode array (PDA) detector

4) Basic conditions:

Mobile phase: Water containing 0.02%NH ₄OAc /ACN

Column: waters acquity UPLC BEH C18 1.7 μm, 2.1 x 50 mm

Detection: MS: waters acquity UPLC SQ Detector and

LC: waters acquity UPLC PDA eλ Detector

5) Basic conditions:

Mobile phase: water containing 10 mmol NH ₄HCO ₃ /ACN

Column: XBridgeTM C18 4.6 x 50 mm-3.5 um

Detection: MS and photodiode array (PDA) detector

6) Basic conditions:

Mobile phase: water containing 0.02%NH ₄OAc /ACN

Column: Welch Ultimate XB-C18 5μm 4.6 x 33mm

Detection: MS and photodiode array (PDA) detector

7) Basic conditions:

Mobile phase: water containing 0.02%NH ₄OAc /ACN

Column: XB-C18 5μm 4.6 x 50mm

Detection: MS and photodiode array (PDA) detector

MDAP Conditions:

1) Acidic conditions:

Instrument: Waters

Column: Xbridge Prep C18 10 um OBD, 19 × 250 mm

Mobile phase: Water containing 0.05%TFA /Acetonitrile.

2) Acidic conditions:

Instrument: Waters

Column: Sunfire Prep C18 column (5 um, 19 × 50 mm)

Mobile phase: Water containing 0.05%TFA /Acetonitrile.

3) Basic conditions:

Instrument: Waters

Column: Xbridge Prep C18 10 um OBD, 19 × 250 mm

Mobile phase: Water containing 10 mM NH ₄HCO ₃/Acetonitrile.

4) Basic conditions:

Instrument: Waters

Colunm: Xbridge Prep C18 column (5 um, 19 × 50 mm)

Mobile phase: Water containing 0.04%Ammonia/Acetonitrile.

5) Basic conditions:

Instrument: PHG016

Column: Xbridge Prep C18 10 um OBD, 19 × 250 mm

Mobile phase: Water containing 0.01%Ammonia + 10 mM NH ₄HCO ₃/Acetonitrile.

Prep-HPLC conditions

1) Acidic conditions:

Instrument: Gilson-281

Column: XBridge Pre C18, 5 μm, OBD 19 × 50 mm

Mobile phase: Water containing 0.1%HCl/Acetonitrile.

2) Acidic conditions:

Instrument: Gilson 281

Column: Gemini C18 21.2 × 100 mm, 5 um

Mobile Phase: Water (0.05%TFA) /Acetonitrile

3) Basic conditions:

Instrument: Gilson-281

Column: XBridge Pre C18, 5 μm, OBD 19 × 50 mm

Mobile phase: Water containing 0.1%NH ₄HCO ₃/Acetonitrile.

4) Basic conditions:

Instrument: Gilson 281

Column: Gemini C18 (21.2 × 100 mm, 5 um)

Mobile phase: Water containing 10 mM NH ₄HCO ₃ or 0.05%NH ₃H ₂O/Acetonitrile.

Chiral analysis (HPLC) :

Instrument: agilent 1100, agilent 1200, shimadzu LC-20A;

Column: chiralpak IA, IB, IC, ID, IE, IF, IG, AD-H, AS-H, AY-H; chiralcel OD-H, OJ-H, OZ-H; 5um, 4.6*250mm

Mobile phase: Hexane, MeOH, EtOH, IPA, ACN, DCM;

Wavelength: 214nm, 230nm, 254nm

Chiral PREP (HPLC) :

Instrument: Gilson-281, Waters-2545

Column: chiralpak IA, IB, IC, ID, IE, IF, IG, AD-H, AS-H; chiralcel OD-H, OJ-H; 5um, 2 (3) *25cm

Abbreviations

Ac - acetyl

AcCl - acetyl chloride

ACN - acetonitrile

AIBN - azobisisobutyronitrile

aq. - aqueous

Ar - heteroaromatic

Bn - benzyl

BINAP - (2, 2′-bis (diphenylphosphino) -1, 1′-binaphthyl)

BuLi - butyl lithium

Boc - tert-butoxycarbonyl

conc. - concentrated

CDI - 1, 1′-carbonyldiimidazole

CMBP - (cyanomethylene) tributylphosphorane

Cy - cyclohexyl

DAST - diethylaminosulfur trifluoride

dba - dibenzylideneacetone

DCE - dichloroethane

DCM - dichloromethane

DEAD - diethyl azodicarboxylate

DIAD - diisopropyl azodicarboxylate

DIBAL-H - diisobutylaluminium hydride

DIPEA - N, N-diisopropylethylamine

DMAP - 4-dimethylaminopyridine

DMB - 2, 4-dimethoxybenzyl

DMS - dimethyl sulfide

DMF - N, N-dimethylformamide

DMSO - dimethyl sulfoxide

dppf - 1, 1′-dis (diphenylphosphino) ferrocene

EA - ethyl acetate

Et - ethyl

HATU - (O-7-azabenzotriazol-1-yl) -N, N, N’, N’-tetramethyluronium

hexafluorophosphate)

Hex - hexane

h - hour

hrs - hours

iPr - isopropyl

LAH - lithium aluminium hydride

LiHMDS - lithium bis (trimethylsilyl) amide

MDAP - Mass Directed Auto-Purification

min - minute or minutes

MOM - methoxymethyl

MOMCl - chloromethyl methyl ether

MsCl - methanesulfonyl chloride

NaHMDS - sodium bis (trimethylsilyl) amide

NBS - N-bromosuccinimide

NCS - N-chlorosuccinimide

NMP - N-methyl-2-pyrrolidone

PE - petroleum ether

PhN (OTf) ₂ - N-Phenyl-bis (trifluoromethanesulfonimide)

PMB - p-methoxybenzyl

Pr - propyl

prep-HPLC - preparative HPLC

prep-TLC - preparative Thin Layer Chromatography

PTSA - p-toluenesulfonic acid

RT - room temperature

rt - retention time

sat. - saturated

TBAB - tetra-n-butylammonium bromide

TBAF - tetra-n-butylammonium fluoride

TBSCl - tert-butyldimethylsilyl chloride

TBS - tert-butyldimethylsilyl

TEA - triethylamine

Temp. - temperature

TFA - trifluoroacetic acid

THF - tetrahydrofurane

THP - tetrahydropyran or tetrahydropyranyl

TMS - trimethylsilyl

TMSCl - trimethylsilyl chloride

X - halide

Description 1

N- (2, 4-dim ethoxybenzyl) thiazol-2-amine (D1)

A solution of 2, 4-dimethoxybenzaldehyde (43 g, 0.26 mol) and thiazol-2-amine (20 g, 0.20 mmol) in toluene (300 mL) was stirred at reflux overnight under N ₂. The reaction mixture was concentrated. The residue was dissolved in MeOH (300 mL) , cooled to 0℃, and added NaBH ₄ (9.1 g, 0.24 mol) in portions at 0℃. Then the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with water, extracted with EA, concentrated and purified by column chromatography on silica gel (PE/EA = 2/1) to give the title compound (22 g, 44%) as a white solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.26-7.21 (m, 1H) , 7.09 (d, J = 3.6 Hz, 1H) , 6.47-6.41 (m, 3H) , 5.68 (s. 1H) , 4.38 (s, 2H) , 3.84 (s, 3H) , 3.79 (s, 3H) .

Description 2

N- (2, 4-dimethoxybenzyl) isoxazol-3-amine (D2)

D2 was prepared using a similar procedure to that described for D1.

Description 3

N- (2, 4-dimethoxybenzyl) -6-fluoropyridin-2-amine (D3)

To a solution of 2, 6-difluoropyridine (6.12 g, 53.2 mmol) in NMP (30 mL) was added (2, 4-dimethoxyphenyl) methanamine (10.66 g, 63.9 mmol) and DIPEA (13.73 g, 106.4 mmol) at RT. The mixture was stirred at 90℃ overnight. The mixture was cooled to RT and poured into water (450 mL) , filtered to give a yellow solid. The solid dissolved in EA (200 mL) , washed with water (100 mL) and brine (100 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was triturated with PE (150 mL) to give the title compound (11.50 g, 82%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.43 (q, J= 8.0 Hz, 1H) , 7.20 (d, J= 8.0 Hz, 1H) , 6.47 (d, J= 2.4 Hz, 1H) , 6.43 (dd, J= 8.4, 2.8 Hz, 1H) , 6.20 (dd, J= 8.0, 2.4 Hz, 1H) , 6.11 (dd, J= 8.0, 2.4 Hz, 1H) , 4.98 (br s, 1H) , 4.38 (d, J= 6.0 Hz, 2H) , 3.83 (s, 3H) , 3.79 (s, 3H) .

Description 4

4-fluorobenzo [d] oxazol-2 (3H) -one (D4)

A mixture of 2-amino-3-fluorophenol (7.6 g, 59.8 mmol) and CDI (11.6 g, 71.8 mmol) in DCM (150 mL) and ACN (50 mL) was stirred at RT overnight. The reaction mixture was concentrated and purified by flash chromatography on silica gel, eluting with PE/EA (10∶1) to give the title compound (8.2 g, 89%) as a brown solid. ¹H NMR (300 MHz, CDCl ₃) : δ 9.10 (br s, 1H) , 7.12-6.93 (m, 3H) .

Description 5

7-fluorobenzo [d] oxazol-2(3H) -one (D5)

D5 was prepared using a similar procedure to that described for D4.

Description 6

6-bromo-4-fluorobenzo [d] oxazol-2 (3H) -one (D6)

To a solution of 4-fluorobenzo [d] oxazol-2 (3H) -one (6.1 g, 39.9 mmol) in ACN (120 mL) was added NBS (7.8 g, 43.9 mmol) in portions at RT. The mixture was stirred at RT for 6 hrs. The solvent was removed under reduced pressure. The residue was dissolved in EA (50 mL) . And then the solution was washed with H ₂O (30 mL×2) , sat. NaHCO ₃ (30 mL×2) , brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column (PE/EA = 5/1 to 3/1) to give the title compound (8.8 g, 95%) as a brown solid. MS (ESI) : C ₇H ₃BrFNO ₂ requires 231; found 232 [M+H] ⁺.

Description 7

6- (benzylthio) -4-fluorobenzo [d] oxazol-2 (3H) -one (D7)

A mixture of 6-bromo-4-fluorobenzo [d] oxazol-2 (3H) -one (8.8 g, 37.9 mmol) , BnSH (7.1 g, 56.9 mmol) , Xantphos (7.7 g, 13.3 mmol) , Pd ₂ (dba) ₃ (10.4 g, 11.4 mmol) and DIPEA (9.8 g, 75.8 mmol) in 1, 4-dioxane (100 mL) was stirred at 100℃ overnight. The reaction mixture was then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 10/1 to 1/1) to give the title compound (10.3 g, 98.8%) as an orange solid. MS (ESI) : C ₁₄H ₁₀FNO ₂S requires 275; found 274 [M-H] ^-.

Description 8

4-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonyl chloride (D8)

4-fluorobenzo [d] oxazol-2 (3H) -one (500 mg, 53.3 mmol) was added in portions to ClSO ₃H (3 mL) at -20℃ with stirring. The mixture was stirred at RT for 2 hrs and stirred at 70℃ for 1.5 hrs. The mixture was cooled to RT and poured slowly into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated to give the crude title compound (550 mg, 67%) as a brown solid. ¹H NMR (300 MHz, DMSO-d ₆) : δ 12.30 (s, 1H) , 7.26 (s, 1H) , 7.22 (d, J= 9.6 Hz, 1H) .

Description 9

7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonyl chloride (D9)

D9 was prepared using a similar procedure to that described for D8.

Description 10

N- (2, 4-dim ethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D10)

A solution of N- (2, 4-dimethoxybenzyl) thiazol-2-amine (325 mg, 1.3 mmol) in THF (6 mL) was cooled to -78℃ and a solution of LiHMDS (1 M in THF, 2.5 mL, 2.5 mmol) was added dropwise. The reaction was allowed to warm to RT for 0.5 hrs. 4-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonyl chloride (252 mg, 1.0 mmol) was then added at -78℃. The reaction was stirred at -40℃ for 3 hrs. The reaction mixture was poured into sat. NH ₄Cl and extracted with EA. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with PE/EA =10/1 to give the title compound (80 mg, 17%) as a brown solid. ¹H NMR (300 MHz, DMSO-d ₆) : δ 7.71-7.29 (m, 4H) , 7.01-6.98 (m, 1H) , 6.48-6.38 (m, 2H) , 5.05 (s, 2H) , 3.77 (s, 6H) .

Descriptions 11-15

D11 to D15 were prepared using a similar procedure to that described for D10.

D11: N- (2, 4-dimethoxybenzyl) -4-fluoro-N- (6-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D12: N- (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D13: N- (2, 4-dimethoxybenzyl) -7-fluoro-N- (6-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D14: N- (2, 4-dimethoxybenzyl) -7-fluoro-N- (isoxazol-3-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D15: N- (2, 4-dimethoxybenzyl) -4-fluoro-N- (5-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

Description 16

N, N-bis (2, 4-dimethoxybenzyl) -4-fiuoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D16)

To a solution of bis (2, 4-dimethoxybenzyl) amine (1.5 g, 4.8 mmol) in DCM (50 mL) was added TEA (1.2 g, 12.0 mmol) at 0℃. Then the mixture was stirred at 0℃ for 30 min. Then 4-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonyl chloride (1.0 g, 4.0 mmol) was added at 0℃. Then the mixture was stirred at RT for 5 hrs. The mixture was concentrated in vacuo. The residue was purified by column chromatography on C18 (ACN/H ₂O = 30-70%) to give the title compound (1.7 g, 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.74 (s, 1H) , 7.41 (d, J= 1.2 Hz, 1H) , 7.31 (dd, J= 9.6, 1.2 Hz, 1H) , 7.03 (d, J= 8.4 Hz, 2H) , 6.42 (dd, J= 8.4, 2.4 Hz, 2H) , 6.37 (d, J= 2.4 Hz, 2H) , 4.27 (s, 4H) , 3.71 (s, 6H) , 3.61 (s, 6H) .

Description 17

N, N-bis (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D17)

D17 was prepared using a similar procedure to that described for D16.

Description 18

4-iodothiazole (D18)

To a suspension of 4-bromothiazole (3.00 g, 18.0 mmol) , CuI (171 mg, 0.9 mmol) and NaI (5.40 g, 36.0 mmol) in 1, 4-dioxane (18 mL) was added N ¹, N ²-dimethylethane-1, 2-diamine (159 mg, 1.8 mmol) at RT. The resulting mixture was stirred 105℃ for 28 hrs. The mixture was cooled and poured into water (100 mL) . Ammonia hydrate (25%, 20 mL) was added and extracted with DCM (40 mL×3) . The combined organic phases were washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (PE/EA = 30/1) to give the title compound (2.5 g, 65%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 8.71 (d, J= 2.1 Hz, 1H) , 7.49 (d, J= 2.1 Hz, 1H) .

Description 19

2-iodo-1, 3, 4-thiadiazole (D19)

A mixture of 1, 3, 4-thiadiazol-2-amine (400 mg, 4.0 mmol) , diiodomethane (1.5 mL) , CuI (750 mg, 4.0 mmol) and isopentyl nitrite (1.5 mL) in THF (5 mL) was stirred at 90℃ for 5 hrs. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EA=10/1) to give the title compound (125 mg, 15%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 9.11 (s, 1H) .

Description 20

tert-butyl 3- ( ( (trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1-carboxylate &tert-butyl 4- ( ( (trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-pyrrole-1-carboxylate (D 20)

To a stirring solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.0 g, 5.4 mmol) in THF (anhydrous, 50 mL) was added NaHMDS (2.0 M in THF, 5.4 mL, 10.8 mmol) at -78℃. Then the reaction mixture was stirred at -78℃ for 1 hour. Then a solution of PhN (OTf) ₂ (2.2 g, 6.2 mmol) in THF (50 mL) was followed to add. After stirring at -78℃ for one hour, the resulting reaction mixture was warmed to RT and stirred for an additional one hour. The reaction mixture was quenched with ice-water. EA (100 mL×3) was added to extract the title compound. Then combined organic phases were washed with brine and concentrated. The residue was purified by column chromatograph on silica gel (PE/EA= 100/1 to 30/1) to obtain the title compound (700 mg, 23%) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 5.76-5.71 (m, 1H) , 4.24-4.19 (m, 4H) , 1.48 (s, 9H) .

Description 21

1- (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanone (D21)

To a stirring solution of 1- (2-bromophenyl) ethanone (5.0 g, 25.1 mmol) and 4, 4, 4′, 4′, 5, 5, 5′, 5′-octamethyl-2, 2′-bi (1, 3, 2-dioxaborolane) (7.0 g, 27.6 mmol) in 1, 4-dioxane (150 mL) was added KOAc (9.8 g, 100 mmol) and Pd (PPh ₃) ₄ (1.45 g, 1.25 mmol) . Then the reaction mixture was heated to 100℃ and stirred under N ₂ for 15 hrs. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (PE/EA= 50/1 to 10/1) to give the title compound (1.5 g, 25%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.85-7.83 (m, 1H) , 7.56-7.45 (m, 3H) , 2.62 (s, 3H) , 1.45 (s, 12H) .

Description 22

tert-butyl 3- (2-acetylphenyl) -2, 5-dihydro-1H-pyrrole-1-carboxylate &tert-butyl 4- (2-acetylphenyl) -2, 3-dihydro-1H-pyrrole-1-carboxylate (D22)

To a stirring solution of 1- (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethanone (1.5 g, 6.1 mmol) , the mixture of tert-butyl 3- ( ( (trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1-carboxylate and tert-butyl 4- ( ( (trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-pyrrole-1-carboxylate (1.9 g, 6.0 mmol) in 1.4-dioxane (100 mL) and water (10 mL) was added K ₂CO ₃ (3.28 g, 23.8 mmol) and Pd (PPh ₃) ₄ (343 mg, 0.3 mmol) . Then the reaction mixture was heated to 95℃ and stirred at 95℃ under N ₂ atmosphere for 15 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatograph (PE/EA= 50/1 to 10/1) to give the title compound (1.0 g, 59%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.52-7.31 (m, 4H) , 5.72-5.69 (m, 1H) , 4.45-4.24 (m, 4H) , 2.51-2.49 (m, 3H) , 1.51 (s, 9H) .

Description 23

tert-butyl 3- (2-acetylphenyl) pyrrolidine-1-carboxylate (D23)

To a stirring solution of tert-butyl 3- (2-acetylphenyl) -2, 5-dihydro-1H-pyrrole-1-carboxylate and tert-butyl 4- (2-acetylphenyl) -2, 3-dihydro-1H-pyrrole-1-carboxylate (300 mg, 1.0 mmol) in MeOH (20 mL) was added PtO ₂ (40 mg) . Then the reaction mixture was stirred at H ₂ (1 atm) atmosphere for 20 min. The reaction mixture was filtered and the solid was washed with MeOH (50 mL) . The combined filtrate was concentrated to give the title compound (250 mg, 83%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.62-7.60 (m, 1H) , 7.45-7.40 (m, 2H) , 7.32-7.27 (m, 1H) , 3.95-3.90 (m, 1H) , 3.76-3.72 (m, 1H) , 3.60-3.26 (m, 3H) , 2.60 (s, 3H) , 2.26-2.05 (m, 1H) , 2.02-1.94 (m, 1H) , 1.48-1.46 (m, 9H) .

Description 24

1- (2- (azetidin-1-yl) phenyl) ethanone (D24)

The suspension of 1- (2-bromophenyl) ethanone (1.98 g, 10.0 mmol) , azetidine (1.02 g, 20.0 mmol) , Pd (OAc) ₂, BINAP (1.24 g, 2.0 mmol) and Cs ₂CO ₃ (6.5 g, 20 mmol) in toluene (50 mL) was stirred at 100℃ under N ₂ overnight. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (eluting with PE/EA = 20/1) to give the title compound as a yellow oil (700 mg, 43%) . ¹H NMR (300 MHz, CDCl ₃) : δ 7.54 (dd, J= 7.8 Hz, 1H) , 7.34 (td, J = 8.1, 1.2 Hz, 1H) , 6.76 (t, J = 7.8 Hz, 1H) , 6.54 (d, J= 8.4 Hz, 1H) , 3.84 (t, J= 7.5 Hz, 4H) , 2.57 (s, 3H) , 2.36-2.29 (m, 2H) .

Description 25

tert-butyl 3-hydroxy-3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) azetidine-1-carboxylate (D25)

To a solution of 2- (2-bromophenyl) -2-methyl-1, 3-dioxolane (1.22 g, 5.0 mmol) in dry THF (10 mL) was added dropwise n-BuLi (2.5 M in THF, 2.2 mL, 5.5 mol) at -78℃. The mixture was warmed to RT over 2 hrs. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (855 mg, 5.0 mmol) in dry THF (5 mL) was added dropwise to the reaction mixture via a syringe pump over 1 h at -78℃. The mixture was stirred at RT for 1 h. The reaction mixture was then quenched with sat. NH ₄Cl (10 mL) , extracted with EA (30 mL) , washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography (PE/EA = 5/1) to give the title compound (632 mg, 38%) as a white solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.63-7.60 (m, 1H) , 7.33-7.29 (m, 3H) , 4.92 (s, 1H) , 4.39-4.58 (m, 2H) , 4.18-4.15 (m, 2H) , 4.10-4.05 (m, 2H) , 3.87-3.82 (m, 2H) , 1.75 (s, 3H) , 1.46 (s, 9H) .

Description 26

tert-butyl 3-fluoro-3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) azetidine-1-carboxylate (D26)

To a solution of tert-butyl 3-hydroxy-3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) azetidine-1-carboxylate (632 mg, 1.89 mmol) in DCM (10 mL) was added dropwise DAST (1.0 M, 2.26 mL, 2.26 mmol) at 0℃. Then the mixture was stirred at RT for 0.5 hrs. To the reaction mixture was added sat. NaHCO3 (aq., 10 mL) , extracted with EA (30 mL) , washed with water (20 mL) and brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated to give the crude title compound (635 mg, 100%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.69-7.66 (m, 1H) , 7.39-7.31 (m, 3H) , 4.51 (d, J = 2.4 Hz, 2H) , 4.44 (d, J= 1.8 Hz, 2H) , 4.01-3.97 (m, 2H) , 3.72-3.68 (m, 2H) , 1.72 (s, 3H) , 1.45 (s, 9H) .

Description 27

tert-butyl 3-methoxy-3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) azetidine-1-carboxylate (D27)

To a solution of tert-butyl 3-hydroxy-3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) azetidine-1-carboxylate (500 mg, 1.49 mmol) in DMF (10 mL) was added NaH (119 mg, 2.98 mmol, 60%in mineral oil) portionwise at 0℃. The mixture was stirred at the same temperature for 30 min, and then stirred at RT for another 30 min before CH ₃I (254 mg, 1.79 mmol) was added. The reaction solution was stirred at RT for 18 hrs. The reaction was quenched with H ₂O (100 mL) and the resulting solution was extracted with EA (100 mL) . The organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and the filtrate was concentrated. The residue was purified by chromatography column on silica gel (PE/EA = 5/1) to give the title compound as a yellow oil. (450 mg, 87%) . ¹H NMR (400 MHz, CDCl ₃) : δ 7.70 (d, J = 10.0 Hz, 1H) , 7.38-7.20 (m, 3H) , 4.35 (d, J= 13.2 Hz, 2H) , 4.27 (d, J= 13.2 Hz, 2H) , 4.00 (brs, 2H) , 3.74 (t, J= 8.8 Hz, 2H) , 3.02 (s, 3H) , 1.76 (s, 3H) , 1.46 (s, 9H) .

Description 28

tert-butyl 3- (2-acetylphenyl) -3-fluoroazetidine-1-carboxylate (D28)

To a solution of tert-butyl 3-fluoro-3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) azetidine-1-carboxylate (635 mg, 1.88 mmol) in THF/H ₂O (10∶1, 11 mL) was added PTSA·H ₂O (36 mg, 0.19 mmol) at RT and the mixture was stirred at 60℃ for 4 hrs. Then the mixture was cooled to RT, added sat. NaHCO ₃ (aq., 10 mL) , extracted with EA (30 mL) , washed with brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography (PE/EA = 10/1) to give the title compound (511 mg, 93%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.58-7.44 (m, 4H) , 4.47-4.30 (m, 2H) , 3.96-3.32 (m, 2H) , 2.57 (s, 3H) , 1.45 (s, 9H) .

Description 29

D29 was prepared using a similar procedure to that described for D28.

D29: tert-butyl 3- (2-acetylphenyl) -3-methoxyazetidine-1-carboxylate

Description 30

tert-butyl 2- (1-hydroxyethyl) benzylcarbamate (D30)

To a solution of 2-acetylbenzonitrile (3 g, 20.7 mmol) in THF (60 mL) was added LAH (2.36 g, 62.1 mmol) in portions at 0℃. Then the mixture was stirred at 75℃ for 8 hrs. The mixture was cooled to 0℃. To the mixture was added water (2.36 mL) , 15%aq. NaOH solution (2.36 mL) and water (7.08 mL) , sequentially. The resulting mixture was stirred at 0℃ for 10 min, then filtered. To the filtrate was added water (12 mL) , K ₂CO ₃ (5.71 g, 41.4 mmol) and (Boc) ₂O (5.86 g, 26.9 mmol) . The reaction mixture was stirred at RT for 30 min. The mixture was diluted with water (100 mL) and further extracted with EA (50 mL×3) . The combined organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with PE/EA=3/1, to give the title compound (4.8 g, 92.4%) as a purple oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.53 (d, J= 7.5 Hz, 1H) , 7.36-7.23 (m, 3H) , 5.24-5.16 (m, 1H) , 4.98-5.01 (m, 1H) , 4.37 (d, J= 6.9 Hz, 2H) , 2.51 (brs, 1H) , 1.53 (d, J= 6.6 Hz, 3H) , 1.45 (s, 9H)

Description 31

1- (2-amino-3-methylphenyl) ethanone (D31)

To a solution of 2-amino-3-methylbenzoic acid (0.3 g, 2.0 mmol) in THF (15 mL) was added MeLi solution (4.3 mL, 6.88 mmol, 1.6M in Et ₂O) dropwise at 0℃ under N ₂. The reaction was stirred at 0℃ for 2 hrs, and then quenched with sat. NH ₄Cl (10 mL) . The organic phase was removed under reduced pressure and the aqueous layer was extracted with DCM (20 mL×3) . The combined organic phase was dried over Na ₂SO ₄ and concentrated. The residue was purified by silica gel chromatography (PE/EA=15/1 to 3/1) to afford the title compound as a brown solid (0.25 g, 85%) . ¹H NMR (400 MHz, CDCl ₃) : δ 7.64 (d, J = 8.0 Hz, 1H) , 7.20 (d, J = 7.2 Hz, 1H) , 6.67 -6.55 (m, 1H) , 6.41 (s, 2H) , 2.59 (s, 3H) , 2.16 (s, 3H) .

Description 32

2-acetyl-6-methylbenzonitrile (D32)

To a suspension of 1- (2-amino-3-methylphenyl) ethanone (223 mg, 1.5 mmol) in H ₂O (1.5 mL) was added acetic acid (1.11g, 6 mmol) and 37%aq. HCl (0.75 mL, 7.5 mmol) at RT. The resulting suspension was refluxed for 5 min. Then the mixture was cooled to 0℃ and a solution of NaNO ₂ (114 mg, 1.65 mmol) in H ₂O (0.5 mL) was slowly added. The red suspension was warmed to RT and stirred for 2 hrs at 20℃. A powder of NaHCO ₃ was added in portions to adjust pH= 7 at ice-bath. NaCN (129 mg, 2.64 mmol) and CuCN (121 mg, 1.35 mmol) were added in a suspension of H ₂O/toluene (5.5 ml/14 mL) . A solution of the diazonium salt was slowly added to the cyanocuprate reagent at ice-bath. The mixture was stirred at RT for 1 hr, then stirred at 65℃ for another 1 hr. The mixture was extracted with EA (20 mL×2) and the combined organic phase was washed with water (50 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified with silica gel chromatography (PE/EA= 15/1 to 2/1) to afford the title compound as a brown solid (70 mg, 30%) . MS (ESI) : C ₁₀H ₉NO requires 159; found 160 [M+H] ⁺.

Description 33

methyl 1- (pyridin-4-yl) cyclopropanecarboxylate (D33)

To a solution of methyl 2- (pyridin-4-yl) acetate (4.20 g, 27.8 mmol) in DMF (50 mL) was added NaH (2.23 g, 55.6 mmol, 60%in mineral oil) at 0℃ and the mixture was stirred at RT under N2 for 1 hour. Then the mixture was cooled to 0℃, 1, 2-dibromoethane (5.23 g, 27.8 mmol) in DMF (10 mL) was added dropwise. The reaction solution was stirred at 20℃ overnight. Then the mixture was poured into water (250 mL) , extracted with EA (150 mL×2) . The combined organic phase was washed with H ₂O (100 mL) and brine (150 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE to PE/EA= 3/1 to PE/EA/DCM= 2/1/1) to give the title compound (4.09 g, 83%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 8.55-8.54 (m, 2H) , 7.26-7.25 (m, 2H) , 3.65 (s, 3H) , 1.67-1.65 (m, 2H) , 1.23-1.20 (m, 2H) .

Description 34

1- (pyridin-3-yl) cyclopropanecarbonitrile (D34)

D34 was prepared using a similar procedure to that described for D33.

Description 35

1- (pyridin-2-yl) cyclopropanecarbonitrile (D35)

To a solution of 2- (pyridin-2-yl) acetonitrile (10.0 g, 84.7 mmol) and 1, 2-dibromoethane (20.7 g, 110 mmol) in ACN (120 mL) at RT was added N-benzyl-N, N-diethylethanaminium bromide (4.60 g, 16.9 mmol) . Then a solution of NaOH (40%, 27.1 g in 40 mL of water, 678 mmol) was added. The resulting mixture was stirred at 55℃ overnight. The mixture was poured into water (100 mL) and extracted with EA (200 mL × 2) . The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 10/1) to give the title compound (8.8 g, 72%) as a slight yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 8.45 (d, J= 4.4 Hz, 1H) , 7.72-7.65 (m, 2H) , 7.17-7.14 (m, 1H) , 1.83-1.80 (m, 2H) , 1.72-1.69 (m, 2H) .

Description 36

methyl 3-oxo-3- (pyridin-3-yl) propanoate and (Z) -methyl 3-hydroxy-3- (pyridin-3-yl) acrylate (D36)

A solution of dimethyl carbonate (14.9 g, 165 mmol) in toluene (100 mL) was added NaH (60%in mineral oil, 10.0 g, 248 mmol) . Then the mixture was heated to reflux and a solution of 1- (pyridin-3-yl) ethanone (10.0 g, 82.6 mmol) in toluene (20 mL) was added dropwise. After addition the mixture was refluxed for 3 hrs. Then the mixture was cooled to 0℃ and acetic acid (10 mL) was added dropwise to quench the reaction. The mixture was filtered and the filtrate was poured into ice water (100 mL) followed by extraction of EA (100 mL × 2) . The combined organic phases were dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography (PE/EA= 20/1 to 10/1 to 1/1) to give the title compound (9.8 g, 66%) as a yellow oil. NMR showed that the two isomers were in a ratio of 2∶1. ¹H NMR (300 MHz, CDCl ₃) : δ 12.47 (br s, 0.33H) , 9.15 (d, J= 2.1 Hz, 0.67H) , 8.99 (d, J= 2.1 Hz, 0.33H) , 8.82 (dd, J= 4.8, 1.5 Hz, 0.67H) , 8.68 (dd, J= 4.8, 1.5 Hz, 0.33H) , 8.26-8.22 (m, 0.67H) , 8.08-8.04 (m, 0.33H) , 7.45 (dd, J= 8.1, 4.8 Hz, 0.67H) , 7.37 (dd, J= 7.8, 4.8 Hz, 0.33H) , 5.72 (s, 0.33H) , 4.03 (s, 1.34H) , 3.82 (s, 1H) , 3.77 (s, 2H) .

Description 37

methyl 1-nicofinoylcyclopropanecarboxylate (D37)

A mixture of methyl 3-oxo-3- (pyridin-3-yl) propanoate and (Z) -methyl 3-hydroxy-3- (pyridin-3-yl) acrylate (2∶1, 9.80 g, 41.1 mmol) , 1, 2-dibromoethane (7.72 g, 41.1 mmol) , K ₂CO ₃ (17.0 g, 123 mmol) and TBAB (1.32 g, 4.11 mmol) in ACN (150 mL) was stirred at 70℃ for 4 days. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EA (100 mL) and water (100 mL) . The organic phase was separated and the aqueous phase was extracted with EA (100 mL) . The combined organic phase was dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography (PE/EA= 3/1 to 2/1 to 1/1) and further purified by column chromatography on C18 (45-60%ACN in water) to give the title compound (2.02 g, 26%) as a yellow oil. MS (ESI) : C ₁₁H ₁₁NO ₃ requires 205; found 206 [M+H] ⁺.

Description 38

methyl 1- (hydroxy (pyridin-3-yl) methyl) cyclopropanecarboxylate (D38)

To a solution of methyl 1-nicotinoylcyclopropanecarboxylate (2.00 g, 9.76 mmol) in methanol (30 mL) at 5℃ was added NaBH ₄ (1.48 g, 39.0 mmol) in portions. After the addition the mixture was stirred at RT for 2 hrs. Then the mixture was concentrated and the residue was dissolved in water (20 mL) . The mixture was extracted with EA (20 mL×2) . The combined organic phases were dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 4/1 to 2/1) to give the title compound (1.51 g, 75%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 8.61 (s, 1H) , 8.48 (d, J= 4.8 Hz, 1H) , 7.78 (d, J= 8.1 Hz, 1H) , 7.29-7.25 (m, 1H) , 4.81 (s, 1H) , 3.92 (br s, 1H) , 3.64 (s, 3H) , 1.45-1.38 (m, 1H) , 1.33-1.26 (m, 1H) , 1.05-0.98 (m, 1H) , 0.95-0.86 (m, 1H) .

Description 39

methyl 1- (pyridin-3-ylmethyl) cyclopropanecarboxylate (D39)

To a solution of methyl 1- (hydroxy (pyridin-3-yl) methyl) cyclopropanecarboxylate (1.51 g, 7.29 mmol) in methanol (30 mL) was added HCl/MeOH (6 M, 3mL) and Pd/C (10%w/w, 0.5 g) . The mixture was stirred under H2 (50 psi) at 50℃ for 2 days. The mixture was filtered through celite and the filtrate was concentrated to give the title compound (1.35 g, 96%) as a yellow oil which was used for next step directly. MS (ESI) : C ₁₁H ₁₃NO ₂ requires 191; found 192 [M+H] ⁺.

Description 40

1- (1- (pyridin-3-yl) cyclopropyl) ethanone (D40)

To a solution of 1- (pyridin-3-yl) cyclopropanecarbonitrile (2.14 g, 14.9 mmol) in THF (50 mL) was added dropwise MeMgBr (5.45 mL, 16.3 mmol, 3M in Et ₂O) at 0℃. The reaction was stirred at 70℃ for 4 hrs. Then cooled to RT and treated with 1N HCl (aq., 40 mL) , added sat. NaHCO ₃ (aq. ) to pH＞ 7, extracted with EA (50 mL×4) . The combined organic phase was washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE to PE/EA= 2/1) to give the title compound (2.05 g, 86%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 8.64 (d, J= 1.5 Hz, 1H) , 8.57-8.55 (m, 1H) , 7.70-7.66 (m, 1H) , 7.32-7.28 (m, 1H) , 2.014 (s, 3H) , 1.70-1.66 (m, 2H) , 1.22-1.19 (m, 2H) .

Description 41

1- (1- (pyridin-2-yl) cyclopropyl) ethanone (D41)

D41 was prepared using a similar procedure to that described for D40.

Description 42

(1- (pyridin-4-yl) cyclopropyl) methanol (D42)

To a solution of methyl 1- (pyridin-4-yl) cyclopropanecarboxylate (1.06 g, 6.0 mmol) in THF (12 mL) was added LAH (456 mg, 12.0 mmol) in portions at 0℃ under N ₂. The mixture was stirred at RT for 0.5 hrs. To the mixture was added dropwise H ₂O (0.45 mL) , 15%NaOH (aq., 0.45 mL) and H ₂O (1.35 mL) at 0℃. The mixture was stirred at RT for 15 min, then added MgSO ₄ and stirred for 15 min. The suspension was filtered and concentrated to give the title compound (807 mg, 90%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 8.45-8.43 (m, 2H) , 7.22-7.20 (m, 2H) , 3.78 (s, 2H) , 2.59 (brs, 1H) , 1.00-0.97 (m, 4H) .

Description 43

1- (pyridin-4-yl) cyclopropanecarbaldehyde (D43) ``

To a solution of (1- (pyridin-4-yl) cyclopropyl) methanol (658 mg, 4.42 mmol) in DCM (40 mL) was added Dess-Martin Reagent (2.25 g, 5.30 mmol) in portions at 0℃ under N ₂. The mixture was stirred at RT overnight. To the mixture was added water (80 mL) , added sat. NaHCO3 (aq. ) to pH ＞ 7. The resulting solution was extracted with DCM (40 mL×2) . The combined organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM to DCM/MeOH= 50/1) to give the title compound (635 mg, 98%) as a red oil. ¹H NMR (400 MHz, CDCl ₃) : δ 9.18 (s, 1H) , 8.61-8.59 (m, 2H) , 7.26-7.23 (m, 2H) , 1.67-1.63 (m, 2H) , 1.49-1.45 (m, 2H) .

Description 44

1- (1- (pyridin-4-yl) cyclopropyl) ethanol (D44)

To a solution of 1- (pyridin-4-yl) cyclopropanecarbaldehyde (714 mg, 4.86 mmol) in THF (20 mL) was added dropwise MeMgBr (3.235 mL, 9.71 mmol, 3M in Et ₂O) at -78℃ under N ₂. The mixture was stirred at RT for 0.5 hrs. To the mixture was added sat. NH ₄Cl (aq., 10 mL) and water (10 mL) and the resulting solution was extracted with EA (30 mL×3) . The combined organic layer was washed with brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated to give the title compound (574 mg, 72%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 8.53-8.51 (m, 2H) , 7.29-7.27 (m, 2H) , 3.53-3.47 (m, 1H) , 1.13 (d, J= 9.3 Hz, 3H) , 0.99-0.85 (m, 4H) .

Description 45

methyl 1- (pyridin-2-yl) cyclopropanecarboxylate (D45)

To a solution of 1- (pyridin-2-yl) cyclopropanecarbonitrile (2.00 g, 13.9 mmol) in ethanol (20 mL) was added KOH (11.7 g in of 10 mL water, 209 mmol) at RT. The resulting mixture was stirred at 85℃ overnight. After cooled to RT the mixture was acidified with HCl (6 N) to pH = 6. EA (200 mL×3) was added for extraction. The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated to give a brown oil (2.35 g of crude) , which was then dissolved in methanol (30 mL) . To the reaction solution was added SOCl ₂ (5 mL) at 0℃. After the addition the resulting mixture was stirred at RT for 5 hrs. Then the mixture was evaporated under vacuum. The residue was diluted with EA (50 mL) and water (50 mL) . NaHCO ₃ was added to adjust pH = 9. The organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 10/1) to give the title compound (1.65 g, 67%) as a brown oil. ¹H NMR (300 MHz, CDCl ₃) : δ 8.53 (d, J = 5.1 Hz, 1H) , 7.68-7.63 (m, 1H) , 7.48 (dd, J = 8.1, 1.2 Hz, 1H) , 7.20-7.15 (m, 1H) , 3.68 (s, 3H) , 1.70-1.65 (m, 2H) , 1.48-1.44 (m, 2H) .

Description 46

1- (1- (pyridin-2-yl) cyclopropyl) ethanol (D46)

To a solution of 1- (1- (pyridin-2-yl) cyclopropyl) ethanone (1.00 g, 6.21 mmol) in methanol (30 mL) was added NaBH4 (0.590 g, 15.5 mmol) in portions at 0℃. After the addition the resulting mixture was stirred at RT for 30 min. The mixture was diluted with EA (150 mL) and sat. NaHCO ₃ (aq., 30 mL) solution. The organic solution was washed with water (50 mL) and brine (50 mL) , dried over Na ₂SO ₄ and concentrated to give the title compound (820 mg, 81%) as a yellow oil which was used for next step directly. ¹H NMR (300 MHz, CDCl ₃) : δ 8.50-8.47 (m, 1H) , 7.65-7.59 (m, 1H) , 7.15-7.11 (m, 1H) , 7.02 (d, J= 8.1 Hz, 1H) , 5.43 (br s, 1H) , 3.51 (q, J= 6.6 Hz, 1H) , 1.21 (d, J= 6.9 Hz, 3H) , 1.18-1.10 (m, 2H) , 0.91-0.80 (m, 2H) .

Description 47

(E) -methyl 3- (pyridin-3-yl) acrylate (D47)

To a solution of (E) -3- (pyridin-3-yl) acrylic acid (10.0 g, 67.1 mmol) in MeOH (200 mL) was added H ₂SO ₄ (98%, 5 mL) dropwise. The mixture was stirred at 100℃ overnight. sat. Na ₂CO ₃ (aq., 100 mL) was added under ice bath and then EA (200 mL) was added. The aqueous phase was extracted with EA (100 mL×3) . The combined organic phases were dried over Na ₂SO ₄ and concentrated to give the title compound (9.00 g, 82%) as a white solid. ¹H NMR (300 MHz, CDCl ₃) : δ 8.78-8.74 (m, 1H) , 8.63-8.61 (m, 1H) , 7.87-7.83 (m, 1H) , 7.73-7.67 (m, 1H) , 7.73-7.29 (m, 1H) , 3.04 (s, 3H) .

Description 48

1- (1- (piperidin-3-yl) cyclopropyl) ethanone (D48)

A mixture of 1- (1- (pyridin-3-yl) cyclopropyl) ethanone (161 mg, 1.0 mmol) and PtO ₂·3H ₂O (28.1 mg, 0.1 mmol) in AcOH (4 mL) was stirred at 30℃ under H ₂ (50 psi) overnight. The mixture was filtered and concentrated to give the title compound (316 mg of crude) as a yellow oil. MS (ESI) : C ₁₀H ₁₇NO requires 167; found 168 [M+H] ⁺.

Description 49

1- (1- (piperidin-4-yl) cyclopropyl) ethanol (D49)

D49 was prepared using a similar procedure to that described for D48.

Description 50

methyl 3- (piperidin-3-yl) propanoate (D50)

To a solution of (E) -methyl 3- (pyridin-3-yl) acrylate (9.00 g, 55.2 mmol) in CH ₃COOH (60 mL) was added PtO ₂ (1.25 g, 5.52 mmol) . The mixture was stirred at 60℃ under H ₂ atmosphere (50 psi) overnight. The mixture was filtered through celite and the filtrate was concentrated to give title compound (15.0 g of crude) as a yellow oil which was used for next step directly. MS (ESI) : C ₉H ₁₇NO ₂ requires 171; found 172 [M+H] ⁺.

Description 51

tert-butyl 3- (1-acetylcyclopropyl) piperidine-1-carboxylate (D51)

To a solution of 1- (1- (piperidin-3-yl) cyclopropyl) ethanone (1.88 g, 11.2 mmol) in THF (60 mL) and H ₂O (40 mL) was added in portions Na ₂CO ₃ (5.97 g, 56.3 mmol) at RT. The mixture was stirred at RT for 0.5 hrs. Then (Boc) ₂O (2.94 g, 13.5 mmol) was added in portions and the mixture was stirred at RT overnight. To the mixture was added H ₂O (100 mL) , extracted with EA (100 mL) . The organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄, filtered and concentrated. It was purified by flash chromatography on silica gel (PE/EA= 4/1) to give the title compound (2.05 g, 68%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 4.06-4.00 (m, 2H) , 2.75-2.55 (m, 2H) , 1.93 (s, 3H) , 1.68-1.64 (m, 2H) , 1.50-1.45 (m, 12H) , 1.20-1.11 (m, 2H) , 0.91-0.82 (m, 2H) .

Descriptions 52-53

D52 and D53 were prepared using a similar procedure to that described for D51.

D52: tert-butyl 4- (1- (1-hydroxyethyl) cyclopropyl) piperidine-1-carboxylate

D53: tert-butyl 3- (3-methoxy-3-oxopropyl) piperidine-1-carboxylate

Description 54

tert-butyl 3- ( (1- (methoxycarbonyl) cyclopropyl) methyl) piperidine-1-carboxylate (D54)

To a solution of methyl 1- (pyridin-3-ylmethyl) cyclopropanecarboxylate (1.35 g, 7.07 mmol) in acetic acid (20 mL) was added PtO ₂ (0.25 g) . The mixture was stirred under H ₂ (50 psi) at 50℃ for 3 hrs. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (20 mL) . Et ₃N (2.86 g, 28.3 mmol) and (Boc) ₂O (2.30 g, 10.6 mmol ) were added. The mixture was stirred at RT overnight. The mixture was poured in to water (50 mL) and extracted with DCM (50 mL×2) . The combined organic phases were dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 10/1 to 5/1) to give the title compound (1.10 g, 52%) as a colorless oil. ¹H NMR (400 MHz, CDCl ₃) : δ 4.04-3.88 (m, 2H) , 3.65 (s, 3H) , 2.72 (t, J= 12.0 Hz, 1H) , 2.43 (br s, 1H) , 1.84-1.77 (m, 2H) , 1.62-1.55 (m, 2H) , 1.45 (s, 9H) , 1.42-1.38 (m, 2H) , 1.27-1.19 (m, 2H) , 1.13-1.07 (m, 1H) , 0.73-0.66 (m, 2H) .

Descriptions 55-56

D55 and D56 were prepared using a similar procedure to that described for D54.

D55: tert-butyl 2- (1- (1-hydroxyethyl) cyclopropyl) piperidine-1-carboxylate

D56: tert-butyl 2- (1- (methoxycarbonyl) cyclopropyl) piperidine-1-carboxylate

Description 57

methyl 2, 3-dimethylbenzoate (D57)

To a solution of 2, 3-dimethylbenzoic acid (20.0 g, 133 mmol) in MeOH (150 mL) was added H ₂SO ₄ (conc., 3 mL) . The mixture was stirred at 80℃ overnight. The mixture was concentrated to give a residue. The residue was poured into water (300 mL) and quenched with sat. NaHCO ₃ (aq. ) to pH= 7. The mixture was extracted with EA (100 mL×3) . The combined organic layers were dried over Na ₂SO ₄ and filtered. The mixture was concentrated to give the title compound (19.5 g, 89%) as a yellow oil which was used for next step directly. ¹H NMR (400 MHz, CDCl ₃) : δ 7.61 (d, J= 7.6 Hz, 1H) , 7.26 (d, J= 7.6 Hz, 1H) , 7.11 (t, J= 7.6 Hz, 1H) , 3.87 (s, 3H) , 2.44 (s, 3H) , 2.30 (m, 3H) .

Description 58

methyl 2-benzylisoindoline-4-carboxylate (D58)

To a solution of methyl 2, 3-dimethylbenzoate (1.00 g, 6.10 mmol) and NBS (2.20 g, 12.4 mmol) in CCl ₄ (20 mL) was added AIBN (30 mg, 0.18 mmol) . Then the mixture was stirred at 95℃ for 4 hrs under N ₂. The mixture was filtered and the filtrate was concentrated to give the crude product. To the crude product was added phenylmethanamine (1.20 g, 11.6 mmol) and N-benzyl-N, N-diethylethanaminium bromide (200 mg) in toluene (20 mL) . To the mixture was then added NaOH (10 M aq., 10 mL) . The mixture was stirred at RT overnight. The mixture was poured into water (20 mL) and extracted with EA (30 mL×3) . The combined organic phases were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to give a residue. The residue was purified by prep-TLC (PE/EA= 5/1) to give the title compound (800 mg, 49%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.87 (d, J= 7.5 Hz, 1H) , 7.44-7.27 (m, 7H) , 4.34 (s, 2H) , 3.95 (s, 4H) , 3.89 (s, 3H) .

Description 59

2-tert-butyl 4-methyl isoindoline-2, 4-dicarboxylate (D59)

To a solution of methyl 2-benzylisoindoline-4-carboxylate (6.00 g, 22.5 mmol) in MeOH (100 mL) was added Pd/C (10%w/w, 600 mg) and (Boc) ₂O (5.4 g, 24.8 mmol) . The mixture was stirred at 65℃ under H ₂ (50 psi) for 3 hrs. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE/EA= 8/1) to give the title compound (3.0 g, 48%) as a red solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.98-7.93 (m, 1H) , 7.47-7.34 (m, 2H) , 4.85 (d, J= 10.4 Hz, 2H) , 4.69 (d, J= 14.4 Hz, 2H) , 3.91 (s, 3H) , 1.53 (s, 9H) .

Description 60

tert-butyl 3- ( (1- (hydroxymethyl) cyclopropyl) methyl) piperidine-1-carboxylate (D60)

A solution of tert-butyl 3- ( (1- (methoxycarbonyl) cyclopropyl) methyl) piperidine-1-carboxylate (1.10 g, 3.70 mmol) in dry THF (30 mL) was cooled to 5℃ under N ₂. Then LAH (1.0 M in THF, 7.41 mL, 7.41 mmol) was added dropwise. After the addition the mixture was stirred at 5℃ for 30 min. Then 0.5 mL of water was added dropwise under ice bath to quench the reaction. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 3/1) to give the title compound (0.78 g, 78%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 4.07-4.03 (m, 1H) , 3.86 (br s, 1H) , 3.48-3.41 (m, 2H) , 2.76 (t, J= 12.0 Hz, 1H) , 2.45 (dd, J= 12.9, 9.9 Hz, 1H) , 1.88-1.76 (m, 3H) , 1.66-1.57 (m, 1H) , 1.46 (s, 9H) , 1.43-1.34 (m, 2H) , 1.14-0.83 (m, 2H) , 0.46-0.38 (m, 4H) .

Descriptions 61-63

D61-D63 were prepared using a similar procedure to that described for D60.

D61: tert-butyl 3- (3-hydroxypropyl) piperidine-l-carboxylate

D62: tert-butyl 2- (1- (hydroxymethyl) cyclopropyl) piperidine-l-carboxylate

D63: tert-butyl 4- (hydroxymethyl) isoindoline-2-carboxylate

Description 64

2- ( (2-bromobenzyl) oxy) tetrahydro-2H-pyran (D64)

To a solution of (2-bromophenyl) methanol (10.0 g, 53.8 mmol) in dichloromethane (200 mL) was added 4-methylbenzenesulfonic acid (460 mg, 2.67 mmol) and followed with 3, 4-dihydro-2H-pyran (6.75 g, 80.2 mmol) . The mixture was stirred at RT overnight. Then the mixture was washed with brine (200 mL) . The organic layer was dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 10/1) to give the title compound (12.6 g, 87%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.55 (t, J= 6.9 Hz, 2H) , 7.33 (t, J = 7.5 Hz, 1H) , 7.19-7.13 (m, 1H) , 4.87-4.79 (m, 2H) , 4.59 (d, J= 13.2 Hz, 1H) , 3.98-3.91 (m, 1H) , 3.61-3.57 (m, 1H) , 1.93-1.84 (m, 1H) , 1.81-1.76 (m, 2H) , 1.74-1.55 (m, 3H) .

Description 65

1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethanol (D65)

To a solution of 2- ( (2-bromobenzyl) oxy) tetrahydro-2H-pyran (2.70 g, 10.0 mmol) in dry THF (100 mL) at -65℃ under nitrogen was added dropwise slowly t-BuLi (1.3 M in THF, 10 mL, 13.0 mmol) . Then the mixture was stirred at -65℃ for 15 min. To this mixture was added acetaldehyde (1.32 g, 30.0 mmol) . After the addition the mixture was stirred at -65℃ for additional 30 min. Then the mixture was poured into sat. NH ₄Cl (aq., 200 mL) with stirring and extracted with EA (150 mL×2) . The combined organic layers were washed with brine (200 mL) , dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 4/1) to give the title compound (1.80 g, 76%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.57 (dd, J = 7.8, 2.1 Hz, 1H) , 7.41-7.35 (m, 2H) , 7.30-7.25 (m, 1H) , 5.24-5.16 (m, 1H) , 4.91 (dd, J= 50.4, 11.7 Hz, 1H) , 4.77-4.74 (m, 1H) , 4.59 (dd, J= 44.1, 11.4 Hz, 1H) , 3.97-3.84 (m, 1H) , 3.63-3.53 (m, 1H) , 2.98 (d, J= 31.8 Hz, 1H) , 1.85-1.74 (m, 2H) , 1.64-1.52 (m, 7H) .

Description 66

1- (2- (aminomethyl) -3-methylphenyl) ethanol (D66)

To a cooled THF (8 mL) slurry of LAH (380 mg, 10.0 mmol) was added a THF (2 mL) solution of 2-acetyl-6-methylbenzonitrile (0.32 g, 2.0 mmol) at 0℃ under N ₂ atmosphere. The mixture was stirred at 70℃ for 1 hr. Another batch of 2-acetyl-6-methylbenzonitrile (0.25 g, 1.6 mmol) was conducted by the same method. The resulting mixture was combined and quenched with water (0.38 mL) , 2N NaOH (0.38 mL) and water (15 mL) sequentially. The mixture was filtered and the filtrate was extracted with EA (30 mL×2) . The combined organic phase was washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated to afford the title compound (0.53 g, 90%) as a brown oil, which was used in the next step without further purification. MS (ESI) : C ₁₀H ₁₅NO requires 165; found 166 [M+H] ⁺.

Description 67

methyl 2-bromo-3-methylbenzoate (D67)

A mixture of 2-bromo-3-methylbenzoic acid (5 g, 23.25 mmol) in HCl/MeOH (20 ml, 3M, 60.0 mmol) was stirred at 70℃ for 3 hrs. Then the mixture was concentrated under reduced pressure and then added water 40 mL, extracted with EA (20 mL×3) . The organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA= 100-95%) to give the title compound (5 g, 21.38 mmol, 92 %) as a yellow oil. MS (ESI) : C ₉H ₉BrO ₂ requires 228; found 229 [M+H] ⁺.

Description 68

methyl 2-cyano-3-methylbenzoate (D68)

A mixture of methyl 2-bromo-3-methylbenzoate (1 g, 4.37 mmol) , PdCl ₂ (dppf) (0.319 g 0.437 mmol) , CuCN (0.391 g, 4.37 mmol) , and Zn (0.285 g, 4.37 mmol) in DMF (20 mL) , was heated to 130℃ under N ₂ for 2 hrs. A mixture of methyl 2-bromo-3-methylbenzoate (4 g, 17.46 mmol) , PdCl ₂ (dppf) (1.278 g, 1.746 mmol) , CuCN (1.564 g, 17.46 mmol) , and Zn (1.142 g, 17.46 mmol) in DMF (20 mL) , was heated to 130℃ under N ₂ for 2 hrs. The reaction mixture from two batches were combined and poured into water (30 mL) , extracted with EA (20mL×3) . The organic layers were combined and dried over Na ₂SO ₄, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA= 100-50%) to give the title compound (3.1 g, 17.70 mmol, 81%) as a yellow solid. MS (ESI) : C ₁₀H ₉NO ₂ requires 175; found 176 [M+H] ⁺.

Description 69

(2- (aminomethyl) -3-methylphenyl) methanol (D69)

To a solution of methyl 2-cyano-3-methylbenzoate (90 mg, 0.514 mmol) in THF (10 mL) was added LAH (1.1 mL) at 0℃. The reaction mixture was warmed to RT for 0.5 hrs. Then to the reaction mixture was added MeOH (5 mL) dropwise at 0℃. The reaction mixture was then warmed to RT. To the mixture was added EA (10 mL) and sat. Na ₂8 ₂O ₃ (aq., 10 mL) . The organic layer was separated. The aqueous layer was washed with EA (5 mL×3) . The organic layers were combined, dried and concentrated. The reaction gave the title compound (78 mg, 0.444 mmol, 86%) . MS (ESI) : C ₉H ₁₃NO requires 151; found 152 [M+H] ⁺.

Description 70

8-bromo-l, 2, 3, 4-tetrahydronaphthalen-2-amine (D70)

To a solution of 8-bromo-3, 4-dihydronaphthalen-2 (1H) -one (4.45 g, 19.8 mmol) and NH ₄OAc (12.18 g, 158.2 mmol) in MeOH (150 mL) was added NaBH ₃CN (1.50 g, 23.7 mmol) at RT. The reaction was stirred at RT overnight. The mixture was acidified with 2N HCl to adjust PH ＜ 3 and stirred for 10 min. The mixture was concentrated, extracted with DCM (50 mL×2) . The aqueous layer was basified with 1N NaOH to adjust PH ＞10, extracted with DCM (50 mL×3) , dried over Na ₂SO ₄, filtered and concentrated to give the crude title compound (2.50 g, 56%) as a brown solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.39-7.36 (m, 1H) , 7.06-6.94 (m, 2H) , 3.21-3.08 (m, 2H) , 2.90-2.85 (m, 2H) , 2.45-2.37 (m, 1H) , 2.00-1.94 (m, 1H) , 1.60-1.57 (m, 1H) .

Description 71

tert-butyl 2- (1-hydroxyethyl) -6-methylbenzylcarbamate (D71)

To a mixture of 1- (2- (aminomethyl) -3-methylphenyl) ethanol (0.35 g, 2.0 mmol) and TEA (0.6 mL, 6.0 mmol) in DCM (10 mL) was added (Boc) ₂O (0.56 g, 2.4 mmol) at RT. The mixture was stirred at RT overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (PE/EA= 10/1 to 1/1) to afford the title compound as a colorless oil (0.6 g, 70%) . ¹H NMR (300 MHz, CDCl ₃) : δ 7.40 (d, J= 7.8 Hz, 1H) , 7.25 (m, 1H) , 7.14 (d, J = 7.5 Hz, 1H) , 5.26 (s, 1H) , 4.81 (s, 1H) , 4.43 (d, J= 5.1 Hz, 2H) , 2.50 (s, 1H) , 2.40 (s, 3H) , 1.54 (d, J= 6.4 Hz, 3H) , 1.45 (s, 9H) .

Descriptions 72-73

D72 &D73 were prepared using a similar procedure to that described for D71.

D72: tert-butyl 2- (hydroxymethyl) -6-methylbenzylcarbamate

D73: tert-butyl (8-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate

Description 74

2-tert-butyl 8-ethyl 3, 4-dihydroisoquinoline-2, 8 (1H) -dicarboxylate (D74)

A mixture of tert-butyl 8-bromo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (2.0 g, 6.4 mmol) , KOAc (1.3 g, 12.9 mmol) and Pd (dppf) Cl ₂ (0.24 g, 0.3 mmol) in EtOH (20 ml) was stirred at 80℃ under CO (1 atm) overnight. The mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA= 10/1, to give the title compound (1.74 g, 89.1%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.86-7.83 (m, 1H) , 7.32-7.21 (m, 2H) , 4.95 (s, 2H) , 4.37 (q, J = 7.2 Hz, 2H) , 3.66 (t, J = 6.0 Hz, 2H) , 2.91 (t, J = 6.0 Hz, 2H) , 1.50 (s, 9H) , 1.41 (t, J= 7.2 Hz, 3H) .

Description 75

D75 was prepared using a similar procedure to that described for D74.

D75: ethyl 7- ( (tert-butoxycarbonyl) amino) -5, 6, 7, 8-tetrahydronaphthalene-1-carboxylate

Description 76

tert-butyl 8- (hydroxymethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D76)

To a solution of 2-tert-butyl 8-ethyl 3, 4-dihydroisoquinoline-2, 8 (1H) -dicarboxylate (1.4 g, 4.6 mmol) in THF (20 mL) was added LAH (350 mg, 9.2 mmol) in portions at 0℃. The reaction mixture was stirred at RT for 1 hour. The reaction was quenched with water (0.35 mL) , 15%NaOH (aq., 0.35 mL) , water (1.05 mL) sequentially at 0℃. The resulting mixture was stirred at 0℃ for 20 min, then filtered. The filtrate was concentrated. The residue was dissolved with EA (30 mL) and the solution was washed with water (30 mL) , brine (30 mL) . The organic layer was then dried over Na ₂SO ₄, filtered and concentrated to give the title compound (1.15 g, 95.1%) as a brown oil. MS (ESI) : C ₁₅H ₂₁NO ₃ requires 263; found 264 [M+H] ⁺.

Description 77

tert-butyl (8- (hydroxymethyl) -l, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (D77)

To a solution of ethyl 7- ( (tert-butoxycarbonyl) amino) -5, 6, 7, 8-tetrahydronaphthalene-1-carboxylate (1.92 g, 6.0 mmol) in dry THF (30 mL) was added LAH (457 mg, 12.0 mmol) in portions at 0℃. The mixture was stirred and allowed to warm slowly to RT for 3 hrs. To the reaction mixture was added MeOH (10 mL) dropwise and stirred 20 min, then added sat. potassium sodium tatrate tetrahydrate (aq., 20 mL) and stirred 0.5 hrs, then added Na ₂SO ₄ and stirred 1 hour. The mixture was filtered and concentrated. The residue was purified by flash chromatography (PE/EA= 2/1) to give the title compound (1.03 g, 62%) as a white solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.22-7.12 (m, 2H) , 7.08-7.05 (m, 1H) , 4.65-4.59 (m, 3H) , 3.99-3.95 (m, 1H) , 3.19-3.11 (m, 1H) , 2.92-2.88 (m, 2H) , 2.62-2.53 (m, 1H) , 2.09-2.04 (m, 1H) , 1.76-1.66 (m, 1H) , 1.45 (s, 9H) .

Description 78

1- (2-iodophenyl) ethanol (D78)

To a solution of 1- (2-iodophenyl) ethanone (1 g, 4.06 mmol) in MeOH (5 mL) was added NaBH4 (115 mg, 3.02 mmol) at 0℃. Then the mixture was stirred at RT for 3 hrs. The reaction mixture was quenched with water. The solution was concentrated and the residue was purified by flash column chromatography on silica gel, eluting with PE/EA=1/1, to give the title compound as a colourless oil (1 g, 100%) . ¹H NMR (300 MHz, CDCl ₃) : δ 7.81 (dd, J= 7.8, 1.2 Hz, 1H) , 7.57 (dd, J = 7.8, 1.8 Hz, 1H) , 7.39 (td, J = 7.8, 0.6 Hz, 1H) , 6.98 (td, J = 7.8, 1.2 Hz, 1H) , 5.07 (q, J = 6.3 Hz, 1H) , 1.47 (d, J= 6.3 Hz, 3H) .

Description 79

8-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-ol (D79)

D79 was prepared using a similar procedure to that described for D78.

Description 80

1-iodo-2- (1- (methoxymethoxy) ethyl) benzene (D80)

To a solution of 1- (2-iodophenyl) ethanol (1 g, 4.03 mmol) in THF (5 mL) , NaH (300 mg, 7.5 mmol, 60%mineral oil) was added at 0℃. Then the mixture was stirred at RT for 1 hour. MOMCl (2 mL, 26.5 mmol) was added to the reaction mixture. The reaction mixture was stirred at RT overnight. Then the reaction solution was heated to 40℃ and stirred overnight. After quenched with water, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel, eluting with PE, to give the title compound (1 g, 84%) as a colourless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.81 (d, J = 8.1 Hz, 1H) , 7.49 (dd, J = 7.8, 1.5 Hz, 1H) , 7.38 (t, J= 7.5 Hz, 1H) , 6.98 (t, J= 7.5 Hz, 1H) , 4.98 (q, J= 6.3 Hz, 1H) , 4.61 (d, J= 6.6 Hz, 1H) , 4.54 (d, J= 6.6 Hz, 1H) , 3.40 (s, 3H) , 1.44 (d, J= 6.6 Hz, 3H) .

Description 81

ethyl 2, 2-difluoro-2- (2- (1- (methoxymethoxy) ethyl) phenyl) acetate (D81)

A mixture of 1-iodo-2- (1- (methoxymethoxy) ethyl) benzene (3.94 g, 13.6 mmol) , ethyl 2-bromo-2, 2-difluoroacetate (3.3 g, 16.3 mmol) and Cu (1.71 g, 27.2 mmol) was stirred at 55℃ overnight under N ₂. After cooled to RT, the reaction mixture was poured into EA (500 mL) and the resulting solution was filtered. The filtrate was washed with brine (100 mL×3) , dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA=100/1 to 25/1) to give the title compound (3.1 g, 79%) as a colorless oil. ¹H NMR (300 MHz, DMSO-d ₆) : δ 7.69-7.60 (m, 2H) , 7.57-7.53 (m, 1H) , 7.49-7.43 (m, 1H) , 4.98-4.92 (m, 1H) , 4.48 (d, J= 6.6 Hz, 1H) , 4.34-4.25 (m, 3H) , 3.17 (s, 3H) , 1.35 (d, J= 6.3 Hz, 3H) , 1.21 (t, J= 7.2 Hz, 3H) .

Description 82

2, 2-difluoro-2- (2- (1- (methoxymethoxy) ethyl) phenyl) acetamide (D82)

A mixture of ethyl 2, 2-difluoro-2- (2- (1- (methoxymethoxy) ethyl) phenyl) acetate (3.0 g, 10.4 mmol) in NH ₃ (15 mL, 6 M in MeOH) was stirred at 40℃ overnight in a sealed tube. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.2 g, 81%) as colorless oil. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.38 (s, 1H) , 8.11 (s, 1H) , 7.66 (d, J= 7.2 Hz, 1H) , 7.57 (t, J= 7.2 Hz, 1H) , 7.50 (dd, J= 7.2, 1.2 Hz, 1H) , 7.41 (t, J= 7.2 Hz, 1H) , 5.15 (q, J= 6.0 Hz, 1H) , 4.49 (d, J= 6.4 Hz, 1H) , 4.39 (d, J= 6.4 Hz, 1H) , 3.22 (s, 3H) , 1.34 (d, J= 6.0 Hz, 3H) .

Description 83

tert-butyl (2, 2-difluoro-2- (2- (1-hydroxyethyl) phenyl) ethyl) carbamate (D83)

To a solution of 2, 2-difluoro-2- (2- (1- (methoxymethoxy) ethyl) phenyl) acetamide (1.0 g, 3.86 mmol) in THF (1.5 mL) was added BH ₃·S (CH ₃) ₂ (3.9 mL, 38.6 mmol, 10 M in THF) slowly under N ₂ at 0℃. After addition, the mixture was heated to reflux for 3 hrs. Then the reaction solution was cooled to 0℃, 6 M HCl (9.7 mL, 57.9 mmol) was added. The mixture heated to 55℃ and stirred for another 1 hour. Then cooled to 0℃, K ₂CO ₃ (9.5 g, 69.5 mmol) was added, followed by (Boc) ₂O (1.3 g, 5.79 mmol) . The mixture was stirred at RT for 2 hrs. H ₂O (30 mL) was added and the resulting solution was extracted with EA (30 mL×3) . The combined organic extracts were concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound (340 mg, 30%) as a white solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.72 (d, J = 7.6 Hz, 1H) , 7.47-7.73 (m, 2H) , 7.29-7.26 (m, 1H) , 5.30-5.25 (m, 1H) , 4.86-4.84 (m, 1H) , 4.28-4.16 (m, 1H) , 3.64-3.55 (m, 2H) , 1.51 (d, J= 6.4 Hz, 3H) , 1.17 (s, 9H) .

Description 84

tert-butyl 3- (2- (1- (methoxymethoxy) ethyl) phenyl) azetidine-1-carboxylate (D84)

Zn powder (2.0 g, 31 mmol) in a three-neck flask was heated to 210℃ under N ₂ for 10 min and cooled to 70℃, then heated to 210℃ for 10 min and cooled to RT again. DMF (8 mL) and dibromoethane (167 mg, 0.9 mmol) in DMF (1 mL) were added. The suspension was heated to 90℃ and stirred for 30 min, then cooled to RT. TMSCl (32 mg, 0.3 mmol) was added into above solution and the mixture was stirred at RT for 30 min. tert-Butyl 3-iodoazetidine-l-carboxylate (1.7 g, 6.2 mmol) in DMF (4 mL) was added dropwise and the resulting mixture was stirred at 35℃ for 1.5 hrs. 1-iodo-2- (1- (methoxymethoxy) ethyl) benzene (900 mg, 3.1 mmol) and Pd (PPh ₃) ₂Cl ₂ (326 mg, 0.47 mmol) in DMF (8 mL) was added into the flask contained the Zn-reagent obtained above. The mixture was heated to 80℃ for 2 hrs under N ₂, then cooled to RT. The reaction was quenched with water (30 mL) and the resulting solution was extracted with Et ₂O (50 mL×3) . The combined organic layer was concentrated and the residue was purified by Prep-HPLC to give the title product (460 mg, 47%) as a yellow oil. MS (ESI) : C ₁₈H ₂₇NO ₄ requires 321; found 322 [M+H] ⁺.

Description 85

2, 2, 2-trifluoro-1- (3- (2- (1-hydroxyethyl) phenyl) azetidin-1-yl) ethanone (D85)

A solution of tert-butyl 3- (2- (1- (methoxymethoxy) ethyl) phenyl) azetidine-1-carboxylate (460 mg, 1.43 mmol) ) in DCM (3 mL) was added TFA (3 mL) and stirred at RT overnight. The solution was concentrated in vacuo to give the title compound (390 mg, 100 %) as a yellow solid. MS (ESI) : C ₁₃H ₁₄F ₃NO ₂ requires 273; found 274 [M+H] ⁺.

Description 86

tert-butyl 3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (D86)

A mixture of 2, 2, 2-trifluoro-1- (3- (2- (1-hydroxyethyl) phenyl) azetidin-1-yl) ethanone (390 mg, 1.4 mmol) ) and K ₂CO ₃ (988 mg, 7.2 mmol) in MeOH/H ₂O (7 mL/3 mL) was stirred at RT for 2 hrs. Then (Boc) ₂O (435 mg, 2.1 mmol) was added and the mixture was stirred at RT for another 2 hrs. To the mixture was then added water (30 mL) and extracted with Et ₂O (50 mL×3) . The combined organic layer was concentrated and the residue was purified by Prep-HPLC to give the title compound (300 mg, 77%) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 7.53-7.48 (m, 2H) , 7.35-7.29 (m, 2H) , 4.98-5.04 (m, 1H) , 4.35-4.27 (m, 2H) , 4.16-4.10 (m, 1H) , 4.05-3.96 (m, 2H) , 1.47-1.44 (m, 12H) .

Description 87

(2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-methylphenyl) methanamine (D87)

To a solution of (2- (aminomethyl) -3-methylphenyl) methanol (760 mg, 5.03 mmol) in DCM (10 mL) was added TBSCl (758 mg, 5.03 mmol) and TEA (0.736 mL, 5.28 mmol) at 0℃. The reaction mixture was allowed to stir overnight and gradually warmed to RT. Then to the reaction mixture was added H ₂O (10 mL) . The organic layer was separated. The aqueous layer was washed with DCM (10 mL×3) . The organic layers were combined and concentrated. The crude product was added to a silica gel column chromatography, eluting with PE/EA, to give the title compound (790 mg, 59.2 %) as a brown solid. MS (ESI) : C ₁₅H ₂₇NOSi requires 265; found 266 [M+H] ⁺.

Description 88

( (8-bromo-1, 2, 3, 4-tetrahydronaphthalen-2-yl) oxy) (tert-butyl) dimethylsilane (D88)

D88 was prepared using a similar procedure to that described for D87.

Description 89

1-bromo-2- (chloromethyl) -3-fluorobenzene (D89)

A solution of (2-bromo-6-fluorophenyl) methanol (10.0 g, 48.8 mmol) in SO ₂Cl (60 mL) was stirred at 70℃ for 3 hrs. The mixture was concentrated and the crude was purified by column chromatography on silica gel (PE/EA= 20/1) to give the title compound (8.5 g, 78%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.42 (d, J = 8.1, 1H) , 7.28-7.18 (m, 1H) , 7.12-7.04 (m, 1H) , 4.79 (s, 2H) .

Description 90

2- (2-bromo-6-fluorophenyl) acetonitrile (D90)

To a solution of 1-bromo-2- (chloromethyl) -3-fluorobenzene (8.50 g, 38.0 mmol) and TEA (7.70 g, 76.1 mmol) in DMSO (50 mL) was added NaCN (2.60 g, 53.1 mmol) . Then the mixture was stirred at RT overnight. The mixture was poured into water (200 mL) and extracted with EA (200 mL×2) . The combined organic layers were washed with brine (200 mL) , dried over Na ₂SO ₄ and concentrated to give the title compound (7.3 g, 90%) as a white solid, which was used in next step without further purification. ¹H NMR (400 MHz, CDCl ₃) : δ 7.45 (d, J = 17.6 Hz, 1H) , 7.28-7.20 (m, 1H) , 7.14-7.07 (m, 1H) , 3.87 (s, 2H) .

Description 91

2- (2-bromo-6-fluorophenyl) ethanamine (D91)

To a solution of 2- (2-bromo-6-fluorophenyl) acetonitrile (7.30 g, 34.1mmol) in THF (30 mL) was added BH ₃/THF (1 M, 102 mL, 102 mmol) under N ₂. After stirred in reflux for 3 hrs, the mixture was cooled to RT. MeOH (90 mL) and HCl (1 M, aq., 60 mL) were added dropwise to the mixture with stirring. Then the mixture was basified with NaOH (1 M, aq. ) to pH= 11 and extracted with EA (100 mL×2) . The combined organic layer was washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated to give the title compound (7.0 g, 95%) as a yellow oil, which was used in next step without further purification. ¹H NMR (300 MHz, CDCl ₃) : δ7.46-7.34 (m, 1H) , 7.15-6.88 (m, 2H) , 2.94 (d, J= 9.0 Hz, 2H) , 1.91 (s, 2H) .

Description 92

2- (2-bromophenyl) acetamide (D92)

To a round bottom flask was added 2- (2-bromophenyl) acetic acid (1000 mg, 4.65 mmol) and toluene (60 mL) . To the solution was added thionyl chloride (0.339 mL, 4.65 mmol) dropwise. The solution was warmed to 60℃ and stirred overnight. Then the reaction solution was cooled to RT and added to ammonia (30 mL, 139 mmol) (10%in H ₂O) at 0℃. The reaction mixture was warmed to RT, concentrated under reduced pressure, and then added H ₂O (30 ml) and EA (20 mL) . The organic layer was separated, dried and concentrated to give the title compound (430 mg, 43.2 %) as a white solid. MS (ESI) : C ₈H ₈BrNO requires 213; found 214 [M+H] ⁺.

Description 93

2- (2-bromophenyl) ethanamine (D93)

To a round bottom flask was added 2- (2-bromophenyl) acetamide (380 mg, 1.775 mmol) in THF (15 mL) . Then to the reaction mixture was added BH ₃·DMS (2M, 4.44 mL, 8.87 mmol) at 0℃. The reaction mixture was allowed to warm to RT overnight. Then the reaction mixture was added BH ₃·DMS (2M, 4.44 mL, 8.87 mmol) and stirred for another 5 days at the same temperature. The reaction was quenched with MeOH (5 mL) dropwised. Then the solution was concentrated under reduced pressure. The residue was added to a C 18 column, eluting with MeCN/TFA 0.1%in H ₂O. The title compound (250 mg, 70.4%) was collected. MS (ESI) : C ₈H ₁₀BrN requires 199; found 200 [M+H] ⁺.

Description 94

2- (2-bromo-6-fluorophenyl) -N- (2, 4-dimethoxybenzyl) ethanamine (D94)

To a solution of 2- (2-bromo-6-fluorophenyl) ethanamine (7.00 g, 32.1 mmol) in toluene (200 mL) was added 2, 4-dimethoxybenzaldehyde (6.39 g, 38.5 mmol) . After stirred in reflux overnight, the mixture was concentrated to get a crude. The crude was dissolved in MeOH (100 mL) and added NaBH4 (2.44 g, 64.2 mmol) . After the addition the mixture was stirred at RT for 2 hrs. The mixture was quenched with ice-water (50 mL) and extracted with EA (100 mL×2) . The combined organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄ and concentrated to give the title compound (crude, 12 g) as a yellow oil, which was used in next step without further purification. MS (ESI) : C ₁₇H ₁₉BrFNO ₂ requires 367; found 368 [M+H] ⁺.

Description 95

5- ( (2, 4-dimethoxybenzyl) amino) pentan-1-ol (D95)

To a solution of 5-aminopentan-1-ol (10.3 g, 100 mmol) in toluene (100 mL) was added 2, 4-dimethoxybenzaldehyde (16.6 g, 100 mmol) . The resulting mixture was heated to reflux with a Dean-stark apparatus and stirred for 4 hrs. The resulting mixture was cooled to RT and concentrated. The residue was dissolved in MeOH (100 mL) and NaBH ₄ (3.78 g, 100 mmol) was added at 0℃. After stirred at 0℃ for 10 min, the mixture was poured into water (500 mL) and extracted with EA (200 mL×3) . The combined organic layer was washed with brine (200 mL) , dried over Na ₂SO ₄ and concentrated to give the title compound (25 g, 100%) as a yellow oil, which was used for next step directly. ¹H NMR (400 MHz, CDCl ₃) : δ 7.11 (d, J= 8.4 Hz, 1H) , 6.45-6.41 (m, 2H) , 3.81 (s, 3H) , 3.79 (s, 3H) , 3.70 (s, 2H) , 3.63-3.59 (m, 2H) , 2.58 (t, J= 7.2 Hz, 2H) , 1.60-1.49 (m, 4H) , 1.43-1.38 (m, 2H) .

Description 96

4- ( (2, 4-dimethoxybenzyl) amino) butan-1-ol (D96)

To a solution of 4-aminobutan-1-ol (1.0573 g, 11.86 mmol) and 2, 4-dimethoxybenzaldehyde (1.9711 g, 11.86 mmol) in DCM (30 mL) , sodium triacetoxyborohydride (3.27 g, 15.42 mmol) was added in small portions at 0℃. The reaction mixture was stirred for 1 hour at 0℃, then warmed to RT gradually, stirred overnight. The reaction mixture was quenched with sat. NaHCO ₃ solution, extracted by DCM. The DCM layer was washed with H ₂O (30 mL×5) . The combined aqueous layer was extracted with EA (40 mL×2) . The combined EA layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to give the title compound (989 mg, 4.13 mmol, 34.8 %) as a colorless oil. ¹H NMR (400 MHz, CDCl ₃) 7.09 (d, J=8.1 Hz, 1H) , 6.45 (d, J=2.4 Hz, 1H) , 6.42 (dd, J=2.4, 8.1 Hz, 1H) , 3.81 (s, 3H) , 3.79 (s, 3H) , 3.71 (s, 2H) , 3.59-3.54 (m, 2H) , 2.65-2.54 (m, 2H) , 1.72-1.64 (m, 2H) , 1.64-1.57 (m, 2H) . MS (ESI) : C ₁₃H ₂₁NO ₃ requires 239; found 240 [M+H] ⁺.

Description 97

D97 was prepared using a similar procedure to that described for D96.

D97: 2- (2-bromophenyl) -N- (2, 4-dimethoxybenzyl) ethanamine

Description 98

tert-butyl 2, 4-dimethoxybenzyl (5-hydroxypentyl) carbamate (D98)

To a solution of 5- ( (2, 4-dimethoxybenzyl) amino) pentan-1-ol (22.5 g, 88.9 mmol) in DCM (200 mL) was added TEA (18.0 g, 178 mmol) . The mixture was cooled to 0℃ and (Boc) ₂O (19.4 g, 88.9 mmol) was added dropwise. After stirred at 0℃ for 1 hour, the mixture was washed with water (100 mL×2) , brine (100 mL) , dried over Na ₂SO ₄ and then concentrated to give the title compound (31 g, 100%) as a yellow oil, which was used for next step directly. ¹H NMR (300 MHz, CDCl ₃) : δ 7.14-7.02 (m, 1H) , 6.47-6.44 (m, 2H) , 4.40-4.34 (m, 2H) , 3.80 (s, 6H) , 3.64-3.60 (m, 2H) , 3.24-3.12 (m, 2H) , 1.76-1.45 (m, 13H) , 1.38-1.30 (m, 2H) .

Descriptions 99-101

D99-D101 were prepared using a similar procedure to that described for D98.

D99: tert-butyl 2-bromophenylethyl (2, 4-dimethoxybenzyl) carbamate

D100: tert-butyl 2, 4-dimethoxybenzyl (4-hydroxybutyl) carbamate

D101: tert-butyl (2-bromo-6-fluorophenyl) ethyl (2, 4-dimethoxybenzyl) carbamate

Description 102

methyl 2- (2- ( (tert-butoxycarbonyl) (2, 4-dimethoxybenzyl) amino) ethyl) -3-fluorobenzoate (D102)

To a mixture of tert-butyl (2-bromo-6-fluorophenyl) ethyl (2, 4-dimethoxybenzyl) carbamate (6.00 g, 12.8 mmol) , DPPF (1.42 g, 2.56 mmol) and NaOAc (2.01 g, 25.6 mmol) in MeOH (100 mL) was added Pd (OAc) ₂ (575 mg, 2.56 mmol) . Then the mixture was stirred at 130℃ under CO (5 MPa) for 2 days. After cooled the mixture was filtered, and the filtrate was concentrated to get the crude. The crude was purified by column chromatography on silica gel (PE/EA = 10/1) to give the title compound (4.4 g, 77%) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 7.66 (d, J= 6.0 Hz, 1H) , 7.37-6.98 (m, 3H) , 6.51-6.38 (m, 2H) , 4.50-4.25 (m, 2H) , 3.88 (s, 3H) , 3.77 (s, 6H) , 3.57-3.39 (m, 2H) , 3.34-3.20 (m, 2H) , 1.39 (s, 9H) .

Description 103

tert-butyl 2, 4-dimethoxybenzyl (2-fluoro-6- (hydroxymethyl) phenethyl) carbamate (D103)

To a solution of methyl 2- (2- ( (tert-butoxycarbonyl) (2, 4-dimethoxybenzyl) amino) ethyl) -3-fluorobenzoate (2.00 g, 4.48 mmol) in MeOH (50 mL) was added NaBH ₄ (851 mg, 22.4 mmol) under ice-bath. The mixture was stirred at RT overnight, then poured into water (100 mL) and extracted with EA (50 mL×2) . The combined organic layer was washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated to get the crude product. The crude was purified by column chromatography on silica gel (PE/EA= 8/1) to give the title compound (1.8 g, 96%) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 7.22-7.05 (m, 3H) , 7.00-6.87 (m, 1H) , 6.51-6.39 (m, 2H) , 4.73-4.62 (m, 2H) , 4.60 (s, 1H) , 4.41 (s, 2H) ., 3.88-3.75 (m, 6H) , 3.46-3.28 (m, 2H) , 2.94-2.82 (m, 2H) , 1.43 (s, 9H) .

Description 104

tert-butyl 3- (3-oxopropyl) piperidine-1-carboxylate (D104)

To a solution of tert-butyl 3- (3-hydroxypropyl) piperidine-1-carboxylate (6.20 g, 25.7 mmol) in DCM (100 mL) was added Dess-Martin periodinane (16.3 g, 38.6 mmol) at 0℃. The mixture was stirred at 0℃ for 4 hrs. To the mixture was added Na ₂S ₂O ₃ (sat., 100 mL) and Na ₂CO ₃ (sat., 100 mL) . After stirred under ice bath for 5 min, the mixture was extracted with DCM (100 mL×2) . The combined organic layer was washed with Na ₂S ₂O ₃ (sat., 100 mL) and brine (100 mL) , dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 3/1) to give the title compound (4.6 g, 80%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 9.78 (s, 1H) , 3.89-3.85 (m, 2H) , 2.79 (t, J=11.7 Hz, 1H) , 2.49 (t, J=7.2 Hz, 3H) , 1.84-1.78 (m, 1H) , 1.67-1.60 (m, 3H) , 1.57-1.52 (m, 1H) , 1.45 (s, 9H) , 1.39-1.25 (m, 1H) , 1.11-1.07 (m, 1H) .

Descriptions 105-108

D105-D108 were prepared using a similar procedure to that described for D104.

D105: tert-butyl 2, 4-dimethoxybenzyl (5-oxopentyl) carbamate

D106: tert-butyl 2, 4-dimethoxybenzyl ( (2-fluoro-6-formylphenyl) ethyl) carbamate

D107: tert-butyl 4-formylisoindoline-2-carboxylate

D108: tert-butyl 4- (3-oxopropyl) piperidine-1-carboxylate

Description 109

tert-butyl 3- (2-formylallyl) piperidine-1-carboxylate (D109)

To a solution of tert-butyl 3- (3-oxopropyl) piperidine-1-carboxylate (2.00 g, 8.37 mmol) in DCM (30 mL) was added TEA (1.27 g, 12.6 mmol) and N-methyl-N-methylenemethanaminium iodide (1.55 g, 8.37 mmol) . The mixture was stirred at RT for 3 hrs. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE/EA = 10/1) to give the title compound (1.12 g, 53%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 9.55 (s, 1H) , 6.30 (s, 1H) , 6.08 (s, 1H) , 3.85 (d, J= 13.5 Hz, 2H) , 2.80 (t, J= 13.5 Hz, 1H) , 2.48 (br s, 1H) , 2.17 (s, 2H) , 1.79-1.74 (m, 1H) , 1.66-1.61 (m, 2H) , 1.46 (s, 9H) , 1.40-1.33 (m, 1H) , 1.16-1.08 (m, 1H) .

Description 110

D 110 was prepared using a similar procedure to that described for D 109.

D110: tert-butyl 2, 4-dimethoxybenzyl (4-formylpent-4-en-1-yl) carbamate

Description 111

tert-butyl 2, 4-dimethoxybenzyl (3-formylbut-3-en-1-yl) carbamate (D111)

To a solution of tert-butyl 2, 4-dimethoxybenzyl (4-hydroxybutyl) carbamate (1.05 g, 3.09 mmol) and TEA (2.156 mL, 15.47 mmol) in anhydrous DMSO (10 mL) and DCM (5 mL) , pyridine sulfur trioxide (1.034 g, 6.50 mmol) was added in small portions at 0℃ under N ₂. The reaction mixture was stirred for 20 min at 0℃, then warmed to RT for 4 hrs. N, N-dimethyl-methyleneammonium iodide (0.630 g, 3.40 mmol) was added in one portion, the resulting reaction mixture was stirred for 2 hrs. The reaction mixture was poured onto ice/sat. NaHCO ₃ solution, extracted with EA (50 mL) . The organic layer was washed with sat. NH ₄C1 solution and brine, then concentrated to dryness. The residue was purified with C18 chromatography, eluting with ACN/0.05%TFA in H ₂O (ACN%= 40%-100%) . Desired fractions were collected, neutrolized with sat. NaHCO ₃ solution. Most ACN was removed by rotavap. The aqueous layer was extracted with EA (50 mL×2) . Combined organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to give the title compound (856.4 mg, 2.16 mmol, 69.7 %) as a colorless oil. ¹H NMR (400 MHz, CDCl ₃) δ 9.50 (s, 1H) , 7.19-7.01 (m, 1H) , 6.49-6.40 (m, 2H) , 6.32-6.13 (m, 1H) , 5.99 (s, 1H) , 4.45-4.28 (m, 2H) , 3.79 (s, 6H) , 3.39-3.19 (m, 2H) , 2.54-2.36 (m, 2H) , 1.50-1.39 (m, 9H) . MS (ESI) : C ₁₉H ₂₇NO ₅ requires 349; found 372 [M+Na] ⁺.

Description 112

tert-butyl 4- (2-formylallyl) piperidine-1-carboxylate (D112)

To a solution of tert-butyl 4- (3-oxopropyl) piperidine-1-carboxylate (100 mg, 0.414 mmol) in isopropanol (1 mL) , formaldehyde (31 μ1, 0.416 mmol) , pyrrolidine (4 mg, 0.056 mmol) and propionic acid (4.5 mg, 0.061 mmol) were added under N ₂. The reaction mixture was heated at 47℃ for 4 hrs. To a solution of tert-butyl 4- (3-oxopropyl) piperidine-1-carboxylate (93 mg, 0.385 mmol) in isopropanol (1.5 mL) , formaldehyde (0.03 mL, 0.403 mmol) , pyrrolidine (3.1 mg, 0.044 mmol) and propionic acid (3.5 mg, 0.047 mmol) were added under N ₂. The reaction mixture was heated at 47℃ for 3.5 hrs. The two bottles of reaction mixtures were combined and directly purified with C 18 chromatography, eluting with ACN/0.05%TFA in H ₂O (ACN%= 40%-100%) , to give the title compound (112 mg, 54%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ 9.54 (s, 1H) , 6.24 (s, 1H) , 6.06 (s, 1H) , 4.06 (brs, 2H) , 2.64 (t, J=13.1 Hz, 2H) , 2.20 (d, J=6.4 Hz, 2H) , 1.67-1.52 (m, 3H) , 1.45 (s, 9H) , 1.15-0.99 (m, 2H) . MS (ESI) : C ₁₄H ₂₃NO ₃ requires 253; found 276 [M+Na] ⁺.

Description 113

tert-butyl 4- ( (1-formylcyclopropyl) methyl) piperidine-1-carboxylate (D113)

To a suspension of NaH (17 mg, 0.425 mmol) in DMSO (2 mL) , trimethylsulfoxonium iodide (78 mg, 0.355 mmol) in DMSO (2 mL) was added dropwise at RT under N ₂. The reaction mixture was stirred for 20 min, then tert-butyl 4- (2-formylallyl) piperidine-1-carboxylate (60 mg, 0.237 mmol) in DMSO (1.5 mL) was added dropwise. The reaction mixture was stirred for 1 hour at RT, quenched with a few drops of sat. NH ₄Cl solution, diluted with EA (30 mL) and water (20 mL) . The organic layer was separated and concentrated. To a suspension of NaH (17 mg, 0.425 mmol) in DMSO (2 mL) , trimethylsulfoxonium iodide (79 mg, 0.361 mmol) in DMSO (2.5 mL) was added dropwise at RT under N ₂. The reaction mixture was stirred for 20 min, then tert-butyl 4- (2-formylallyl) piperidine-1-carboxylate (61 mg, 0.241 mmol) in DMSO (1.5 mL) was added dropwise. The reaction mixture was stirred for 1 hour at RT, quenched with a few drops of sat. NH ₄Cl solution, diluted with EA (30 mL) and water (20 mL) . The organic layer was separated and concentrated. The residue from two batches were combined and purified with C 18 chromatography, eluting with ACN/0.05%TFA in H ₂O (ACN%= 30%-100%) , to give the title compound (75.5 mg, 0.282 mmol) as a pale yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ 8.70 (s, 1H) , 4.06 (brs, 2H) , 2.65 (t, J=13.1 Hz, 2H) , 1.86-1.73 (m, 1H) , 1.66 (d, J=13.0 Hz, 2H) , 1.59-1.48 (m, 2H) , 1.44 (s, 9H) , 1.21-1.15 (m, 2H) , 1.07 (dq, J=4.3, 12.4 Hz, 2H) , 0.97-0.90 (m, 2H) . MS (ESI) : C ₁₅H ₂₅NO ₃ requires 267; found 290 [M+Na] ⁺.

Description 114

tert-butyl 2, 4-dimethoxybenzyl (4- (hydroxymethyl) pent-4-en-1-yl) carbamate (D114)

To a solution of tert-butyl 2, 4-dimethoxybenzyl (4-formylpent-4-en-1-yl) carbamate (1.00 g, 2.75 mmol) in MeOH (10 mL) was added NaBH4 (157 mg, 4.13 mmol) at 0℃. After stirred at 0℃ for 15 min the mixture was poured into water (50 mL) . The mixture was extracted with EA (50 mL×2) . The combined organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 5/1) to give the title compound (700 mg, 70%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.15-7.05 (m, 1H) , 6.48-6.45 (m, 2H) , 5.03 (s, 1H) , 4.86 (s, 1H) , 4.43-4.35 (m, 2H) , 4.06 (s, 2H) , 3.81 (s, 6H) , 3.24-3.13 (m, 2H) , 2.05-2.00 (m, 2H) , 1.72-1.63 (m, 2H) , 1.46 (s, 9H) .

Description 115

D115 was prepared using a similar procedure to that described for D114.

D115: tert-butyl 2, 4-dimethoxybenzyl (3- (hydroxymethyl) but-3-en-1-yl) carbamate

Description 116

tert-butyl 3- (3-hydroxy-2-methylenebutyl) piperidine-1-carboxylate (D116)

A solution of tert-butyl 3- (2-formylallyl) piperidine-1-carboxylate (1.10 g, 4.35 mmol) in THF (15 mL) was cooled to 0℃ under N ₂ atmosphere. MeMgBr solution (3.0 M in ether, 2.2 mL, 6.6 mmol) was added dropwise. The mixture was stirred at 0℃ for 1.5 hrs. NH ₄Cl (sat., 10 mL) was added to quench the reaction. The mixture was extracted with EA (20 mL×2) . The combined organic layer were washed with brine, dried over Na ₂SO ₄ and concentrated to give the title compound (0.95 g, 81%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 5.13 (s, 1H) , 4.84 (s, 1H) , 4.29-4.21 (m, 1H) , 4.00-3.78 (m, 2H) , 2.90-2.72 (m, 1H) , 2.58-2.38 (m, 1H) , 2.02-1.62 (m, 7H) , 1.45 (s, 9H) , 1.31-1.27 (m, 3H ) , 1.15-1.06 (m, 1H) .

Descriptions 117-119

D 117-D 119 were prepared using a similar procedure to that described for D 116.

D117: tert-butyl 2, 4-dimethoxybenzyl (5-hydroxy-4-methylenehexyl) carbamate

D118: tert-butyl 2, 4-dimethoxybenzyl (4-hydroxy-3-methylenepentyl) carbamate

D119: tert-butyl 4- ( (1- (1-hydroxyethyl) cyclopropyl) methyl) piperidine-1-carboxylate

Description 120

tert-butyl 4- (1-hydroxyethyl) isoindoline-2-carboxylate (D120)

To a solution of tert-butyl 4-formylisoindoline-2-carboxylate (3.50 g, 14.2 mmol) in THF (30 mL) was added MeMgBr (1 M in THF, 21.2 mL, 21.2 mmol) under N ₂ at -65℃. After stirred at -65℃ for 1 hour, the mixture was quenched with sat. NH ₄Cl (aq., 30 mL) and extracted with EA (50 mL×3) . The combined organic phases was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (PE/EA = 8/1) to give the title compound (2.5 g, 67%) as a white solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.36-7.26 (m, 2H) , 7.15 (dd, J= 17.6, 7.2 Hz, 1H) , 4.91 (q, J= 6.4 Hz, 1H) , 4.78-4.63 (m, 4H) , 2.12-2.02 (m, 1H) , 1.52 (s, 9H) , 1.50-1.46 (m, 3H) .

Description 121

D121 was prepared using a similar procedure to that described for D120.

D121: tert-butyl 2, 4-dimethoxybenzyl (2-fluoro-6- (1-hydroxyethyl) phenylethyl) carbamate

Description 122

tert-butyl 3- ( (1- (1-hydroxyethyl) cyclopropyl) methyl) piperidine-1-carboxylate (D122)

ZnEt2 solution (1.0 M in hexane, 17.7 mL, 17.7 mmol) was added dropwise to dry ether (30 mL) at 0℃ under N ₂. Then CH ₂I ₂ (4.73 g, 17.7 mmol) was followed to add dropwise. After the mixture was stirred at 0℃ for 1 hour a solution of tert-butyl 3- (3-hydroxy-2-methylenebutyl) piperidine-1-carboxylate (0.950 g, 3.53 mmol) in dry ether (5 mL) was added dropwise. The resulting mixture was stirred at 0℃ for 10 min and at RT for 2 hrs. NH ₄Cl (sat., 20 mL) was added to quench the reaction. The mixture was extracted with EA (20 mL×2) . The combined organic layers were dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 5/1 to 3/1) to give the title compound (0.43 g, 43%) as yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 4.05-3.93 (m, 2H) , 3.56-3.48 (m, 1H) , 2.77-2.65 (m, 1H) , 2.45-2.39 (m, 1H) , 1.88-1.82 (m, 3H) , 1.69-1.59 (m, 2H) , 1.46 (s, 9H) , 1.17 (d, J= 6.4 Hz, 3H) , 1.10-1.00 (m, 2H) , 0.94-0.88 (m, 1H) , 0.54-0.41 (m, 2H) , 0.35-0.32 (m, 1H) , 0.23-0.21 (m, 1H) .

Descriptions 123-126

D123-D126 were prepared using a similar procedure to that described for D 122.

D123: tert-butyl 2, 4-dimethoxybenzyl (3- (1- (hydroxymethyl) cyclopropyl) propyl) carbamate

D124: tert-butyl 2, 4-dimethoxybenzyl (2- (1- (hydroxymethyl) cyclopropyl) ethyl) carbamate

D125: tert-butyl 2, 4-dimethoxybenzyl (3- (1- (1-hydroxyethyl) cyclopropyl) propyl) carbamate

D126: tert-butyl 2, 4-dimethoxybenzyl (2- (1- (1-hydroxyethyl) cyclopropyl) ethyl) carbamate

Description 127

tert-butyl (2, 4-dimethoxybenzyl) (2- (1-hydroxyethyl) phenylethyl) carbamate (D127)

To a solution of tert-butyl (2-bromophenylethyl) (2, 4-dimethoxybenzyl) carbamate (250 mg, 0.555 mmol) in THF (5 mL) was added n-BuLi (0.8 mL, 1.600 mmol) at -78℃ dropwise and then added acetaldehyde (0.2 mL, 3.54 mmol) at same temperature under N ₂. The reaction mixture was stirred at same temperature for 30 min. To the reaction mixture was warmed to RT and was added H2O (10 mL) and EA (10 mL) . The two layers were separated. The aqueous layer was extracted with EA (10 mL) . The organic layers were combined, dried with Na ₂SO ₄, filtrated and concentrated. The crude product was added to a 120 g C18 reverse phase chromatography and was eluted with H ₂O/ACN = 100%to 0%. The title compound (40 mg, 16.99%) was collected as a light oil. MS (ESI) : C ₂₄H ₃₃NO ₅ requires 415; found 438 [M+Na] ⁺.

Description 128

D 128 was prepared using a similar procedure to that described for D127.

D128: 1- (7- ( (tert-butyldimethylsilyl) oxy) -5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethanol

Description 129

ethyl 2- ( (2- (hydroxymethyl) -6-methylbenzyl) amino) acetate, trifluoroacetic acid salt (D129)

To a solution of (2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-methylphenyl) methanamine (300 mg, 1.13 mmol) in DCM (50 ml) was added ethyl 2-oxoacetate (0.224 ml, 1.13 mmol) and sodium triacetoxyborohydride (240 mg, 1.13 mmol) at RT. The reaction mixture was allowed to stir for 2 hrs, Then to the reaction mixture was added NaOH (aq., 1M, 5 mL) to stop the reaction. To a solution of (2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-methylphenyl) methanamine (390 mg, 1.469 mmol) in DCM (50 ml) was added ethyl 2-oxoacetate (0.291 ml, 1.469 mmol) and sodium triacetoxyborohydride (311 mg, 1.469 mmol) at RT. The reaction mixture was allowed to stir for 2 hrs. Then to the reaction mixture was added NaOH (aq., 1M, 5 mL) to stop the reaction. Two batches of the above reaction mixture were combined. To the mixture was added sat. NaHCO ₃ (aq., 10 mL) and DCM (10 mL) . The two layers were separated. The aqueous layer was washed with DCM (5 mL×2) . The organic layers were combined, dried and concentrated. The crude product was added to a reverse phase column and was eluted with ACN/H ₂O (TFA 5%) . Fraction containing ethyl 2- ( (2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-methylbenzyl) amino) acetate was collected and then freezing dried under reduced vacuum. The title compound (470 mg, 51%) was isolated as a white solid. MS (ESI) : C ₁₃H ₁₉NO ₃ requires 237; found 238 [M+H] ⁺.

Description 130

ethyl 2- ( (tert-butoxycarbonyl) (2- (hydroxymethyl) -6-methylbenzyl) amino) acetate (D130)

To a solution of ethyl 2- ( (2- (hydroxymethyl) -6-methylbenzyl) amino) acetate, Trifluoroacetic acid salt (470 mg, 1.338 mmol) in DCM (50 mL) was added Boc ₂O (0.466 mL, 2.007 mmol) and TEA (0.746 mL, 5.35 mmol) at 0℃. The reaction mixture was allowed to stir for 1 hour and gradually warmed to RT. Then to the reaction mixture was added H ₂O (10 mL) . The organic layer was separated. The aqueous layer was washed with DCM (5 mL×3) . The organic layers were combined and concentrated to afford the title compound (543 mg, 100 %, crude) . MS (ESI) : C ₁₈H ₂₇NO ₅ requires 337; found 360 [M+Na] ⁺.

Description 131

tert-butyl (2-amino-2-oxoethyl) (2- (hydroxymethyl) -6-methylbenzyl) carbamate (D131)

To a microwave vessel was added ethyl 2- ( (tert-butoxycarbonyl) (2- (hydroxymethyl) -6-methylbenzyl) amino) acetate (250 mg, 0.741 mmol) in ammonia (10 ml, 462 mmol) . The reaction vessel was sealed and heated by microwave to 80℃ overnight. After cooling the reaction mixture was concentrated under reduced pressure. The crude product was added to a C18 reverse phase column, eluting with ACN/H ₂O. The title compound (160 mg, 70.0 %) was collected. MS (ESI) : C ₁₆H ₂₄N ₂O ₄ requires 308; found 209 [M-100+H] ⁺.

Description 132

7- ( (tert-butoxycarbonyl) amino) -5, 6, 7, 8-tetrahydronaphthalene-1-carboxylic acid (D132)

The suspension of ethyl 7- ( (tert-butoxycarbonyl) amino) -5, 6, 7, 8-tetrahydronaphthalene-1-carboxylate (1.0 g, 3.13 mmol) and LiOH·H ₂O (658 mg, 15.7 mmol) in EtOH/THF/H ₂O (8.0 mL/4.0 mL/1.0 mL) was stirred at 50℃ overnight. EtOH and THF were removed under reduced pressure. The residue was diluted with H ₂O (50 mL) and the solution was extracted with DCM (30 mL) . The aqueous layer was then acidified to pH ～3 with 6N HC1. The resulting solution was then extracted with EA (50 mL×2) . The combined organic layer was washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated to give the title compound (580 mg, 64%) as a yellow solid. MS (ESI) : C ₁₆H ₂₁NO ₄ requires 291; found 290 [M-H] ^-.

Description 133

tert-butyl (8- (methoxy (methyl) carbamoyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (D133)

To a solution of 7- ( (tert-butoxycarbonyl) amino) -5, 6, 7, 8-tetrahydronaphthalene-l-carboxylic acid (580 mg, 2.0 mmol) , N, O-dimethylhydroxylamine hydrochloride (392 mg, 4.0 mmol) and HATU (1.52 g, 4.0 mmol) in DMF (15 mL) was added DIPEA (774 mg, 6.0 mmol) and DMAP (30 mg, 0.26 mmol) at RT. The mixture was stirred at RT overnight. The reaction solution was diluted with H ₂O (50 mL) and the resulting solution was extracted with EA (30 mL×2) . The combined organic layer was washed with brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with PE/EA = 2/1, to give the title compound (585 mg, 88%) as a white solid. MS (ESI) : C ₁₈H ₂₆N ₂O ₄ requires 334; found 335 [M+H] ⁺

Description 134

tert-butyl 4- (1- (ethoxycarbonyl) cyclopropanecarbonyl) piperidine-1-carboxylate (D134)

tert-Butyl 4- (3-ethoxy-3-oxopropanoyl) piperidine-1-carboxylate (1.81 g, 6.04 mmol) , potassium carbonate (2.505 g, 18.13 mmol) and 1, 2-dibromoethane (1.0 mL, 11.60 mmol) were suspended in DMF (15 mL) under N ₂. The reaction mixture was stirred at 50℃ for 2 days, then cooled down to RT, filtered. The solid was rinsed with EA several times. The filtrate was diluted with water (30 mL) and EA (20 mL) , extracted, the aqueous layer was extracted twice with EA (15 mL×2) . The combined organic layer was concentrated and the residue was purified with C18 reverse phase chromatography (ACN/0.05%TFA in H ₂O, ACN%= 50%-100%) , to give (1.25 g, 63.6%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl ₃) δ 4.21 (q, J=7.1 Hz, 2H) , 4.09 (br, d, J=13.4 Hz, 2H) , 3.33 (tt, J=11.3, 3.6 Hz, 1H) , 2.79 (t, J=12.7 Hz, 2H) , 1.85 (br, d, J=11.7 Hz, 2H) , 1.56-1.48 (m, 2H) , 1.48-1.38 (m, 13H) , 1.28 (t, J=7.1 Hz, 3H) . MS (ESI) : C ₁₇H ₂₇NO ₅ requires 325; found 348 [M+Na] ⁺.

Description 135

tert-butyl 4- ( (1- (ethoxycarbonyl) cyclopropyl) (hydroxy) methyl) piperidine-1-carboxylate (D135)

To a solution of tert-butyl 4- (1- (ethoxycarbonyl) cyclopropanecarbonyl) piperidine-1-carboxylate (1 g, 3.07 mmol) in EtOH (25 mL) , NaBH ₄ (140 mg, 3.70 mmol) was added in small portions at 0℃. The reaction mixture was stirred for 5 min, additional NaBH ₄ (12 mg, 0.317 mmol) was added. The reaction mixture was stirred for 20 min., then quenched with sat. NH ₄Cl (aq. ) . Solvent was removed. The residue was dissolved with EA (20 mL) and water (5 mL) . The two layers were separated. The aqueous layer was extracted with EA (10 mL) again. Combined organic layer was concentrated. The residue was purified with C 18 reverse phase chromatography (ACN/0.05%TFA in water, ACN%= 50%-100%) , to give the title compound (960 mg, 95%) as a colorless thicky oil. ¹H NMR (600 MHz, MeOD-d ₄) δ 4.18-4.05 (m, 4H) , 3.09 (d, J=8.1 Hz, 1H) , 2.69 (brs, 2H) , 2.13-2.05 (m, 1H) , 1.98 (d, J=13.6 Hz, 1H) , 1.63 (dt, J=12.9, 2.9 Hz, 1H) , 1.45 (s, 9H) , 1.26-1.18 (m, 5H) , 1.15-1.07 (m, 2H) , 0.98-0.93 (m, 1H) , 0.90-0.85 (m, 1H) . MS (ESI) : C ₁₇H ₂₉NO ₅ requires 327; found 350 [M+Na] ⁺.

Description 136

ethyl 1- (chloro (piperidin-4-yl) methyl) cyclopropanecarboxylate, trifluoroacetic acid salt (D136)

To a solution of tert-butyl 4- ( (1- (ethoxycarbonyl) cyclopropyl) (hydroxy) methyl) piperidine-1-carboxylate (500 mg, 1.527 mmol) in DCM (7 mL) , sulfurous dichloride (1 mL, 13.70 mmol) was added dropwise at 0℃. The reaction mixture was allowed to rise to RT gradually for 4 hrs, , then quenched with MeOH, and stirred for 30 min. Solvent was removed under vacuum. The crude product was purified with C18 reverse phase chromatography (ACN/0.05%TFA in water, ACN%= 5%-65%) , to give the title compound (537 mg, 98 %) as a pale yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 9.42 (brs, 1H) , 8.88 (brs, 1H) , 4.21-4.07 (m, 2H) , 3.45 (t, J=12.8 Hz, 2H) , 3.15 (d, J=9.3 Hz, 1H) , 2.99-2.71 (m, 3H) , 2.39 (d, J=14.2 Hz, 1H) , 2.00 (d, J=13.9 Hz, 1H) , 1.71-1.58 (m, 1H) , 1.57-1.44 (m, 3H) , 1.25 (t, J=7.2 Hz, 3H) , 1.11-1.01 (m, 1H) , 0.97-0.88 (m, 1H) . MS (ESI) : C ₁₂H ₂₀ClNO ₂ requires 245; found 246 [M+H] ⁺.

Description 137

tert-butyl 4- ( (1- (hydroxymethyl) cyclopropyl) methyl) piperidine-1-carboxylate (D137)

To a cold solution of ethyl 1- (chloro (piperidin-4-yl) methyl) cyclopropanecarboxylate, trifluoroacetic acid salt (537 mg, 1.493 mmol) in THF (10 mL) , LAH (2M, 3 mL, 6.00 mmol) solution was added slowly at 3℃ under N ₂, with temperature ＜ 8℃ during addition. After addition, the reaction mixture was stirred for 1 hour at 3℃. The reaction solution was transferred to a microwave tube under N ₂. The tube was sealed and heated at 60℃ overnight, cooled down to RT, then carefully quenched with MeOH in ice water bath. A few water was added at last. Solvent was removed under vacuum. The residue was suspended in DCM (10 mL) , and added TEA (0.31 mL, 2.224 mmol) and Boc ₂O (325.7 mg, 1.492 mmol) solution in DCM (1 mL) . The reaction mixture was stirred for 2 hrs at RT. Solvent was removed under vacuum. The residue was purified with C18 reverse phase chromatography (ACN/water with 0.05%TFA, ACN%= 45%-100%) to give the title compound (60 mg, 14.92%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 4.07 (brs, 2H) , 3.42 (s, 2H) , 2.69 (t, J=12.5 Hz, 2H) , 1.82-1.66 (m, 3H) , 1.45 (s, 9H) , 1.37-1.27 (m, 2H) , 1.16-1.00 (m, 2H) , 0.42-0.36 (m, 2H) , 0.35-0.29 (m, 2H) . MS (ESI) : C ₁₅H ₂₇NO ₃ requires 269; found 292 [M+Na] ⁺.

Description 138

tert-butyl 4- (2-acetylphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D138)

tert-Butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (3.09 g, 15.53 mmol) , 1- (2-bromophenyl) ethanone (4.0 g, 12.94 mmol) , Pd (dppf) Cl ₂ (300 mg, 0.41 mmol) and K ₂CO ₃ (3.6 g, 25.87 mmol) in 1, 4-dioxane/H ₂O (65 mL/15 mL) was heated at 90℃ overnight under N ₂. The mixture was cooled to RT and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 10/1) to give the title compound (3.5 g, 86%) as a brown oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.55 (d, J= 7.8 Hz, 1H) , 7.44 (td, J = 7.2, 1.2 Hz, 1H) , 7.34 (td, J= 7.5, 1.5 Hz, 1H) , 7.27-7.21 (m, 1H) , 5.54 (brs, 1H) , 4.02 (brs, 2H) , 3.67-3.62 (m, 2H) , 2.50 (s, 3H) , 2.40 (brs, 2H) , 1.47 (s, 9H) .

Description 139

tert-butyl 8-acetyl-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D139)

8-Bromo-1, 2, 3, 4-tetrahydroisoquinoline (4.24 g, 20 mmol) , Pd (OAc) ₂ (0.449 g, 2.0 mmol) , 1, 3-bis (diphenylphosphino) propane (1.650 g, 4.0 mmol) , butyl vinyl ether (13.01 mL, 100 mmol) and K ₂CO ₃ (5.53 g, 40.0 mmol) were dissolved in DMF (50 mL) and H ₂O (6 mL) . The mixture was heated to 80℃ for 16 hrs. After cooling back to RT, 20 mL HCl (3M) was added to the reaction and the mixture was stirred for 1 h. The mixture was then adjusted to PH＞ 7 by addition of NaOH (aq., 3.0 M, 24 mL) solution. And the mixture was extracted by DCM (30mL×3) . The combined organic layer was washed with brine, dried over Na ₂SO ₄ and concentrated. To the residue was added DCM (100 mL) , NaOH (aq., 3.0 M, 40 mL) and Boc ₂O (9.29 mL, 40.0 mmol) . The reaction mixture left stirring overnight. The reaction mixture was then filtered through celite and filter cake was washed with DCM (50 mL) . After separation, the organic layer was washed with brine and dried over Na ₂SO ₄. After concentrated in vacuo, the crude product was purified by silica gel chromatography (PE/EA = 0%to 40%) to give the title compound (4.084 g, 71.9%) . MS (ESI) : C ₁₆H ₂₁NO ₃ requires 275; found 298 [M+Na] ⁺.

Descriptions 140-141

(R) -tert-butyl (8-acetyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate & (S) -tert-butyl (8-acetyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (D140 &D141)

To a solution of tert-butyl (8- (methoxy (methyl) carbamoyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (1.53 g, 4.58 mmol) in THF (15 mL) was added MeLi (8.26 mL, 13.2 mmol, 1.6 M in Et ₂O) dropwise at -78℃. The mixture was stirred at the same temperature for 30 min. The reaction solution was poured into ice-water (50 mL) . The resulting solution was extracted with EA (30 mL × 3) . The combined organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with PE/EA = 2/1) to give racemic compounds (950 mg, 72%) . The compounds were then further separated with chiral column (Chiralpak IF 5um 20mm*250mm, Phase: CO ₂∶MeOH = 80∶20) to give the title compounds (390 mg and 420 mg) . Isomer 1: HPLC (Chiralpak IF 5 um 20*250mm, Phase: CO ₂∶EtOH = 80∶20, rt = 2.85 min; ＞99%ee; ¹H NMR (300 MHz, CDCl ₃) : δ 7.52 (dd, J= 6.6, 1.2 Hz, 1H) , 7.25-7.18 (m, 2H) , 4.63-4.59 (m, 1H) , 3.91-3.85 (m, 1H) , 3.27 (dd, J= 15.6, 4.8 Hz, 1H) , 2.96-2.79 (m, 3H) , 2.57 (s, 3H) , 2.14-2.09 (m, 1H) , 1.46 (s, 9H) . Isomer 2: HPLC (Chiralpak IF 5 um 20*250mm, Phase: CO ₂∶EtOH = 80∶20, rt = 4.33 min; ＞99%ee; ¹H NMR (300 MHz, CDCl ₃) : δ 7.52 (dd, J = 6.6, 1.2 Hz, 1H) , 7.25-7.18 (m, 2H) , 4.63-4.59 (m, 1H) , 3.91-3.85 (m, 1H) , 3.27 (dd, J= 15.6, 4.8 Hz, 1H) , 2.96-2.79 (m, 3H) , 2.57 (s, 3H) , 2.14-2.09 (m, 1H) , 1.46 (s, 9H) .

Description 142

tert-butyl 8- (1-hydroxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D142)

To a solution of tert-butyl 8-acetyl-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (1 g, 3.6 mmol) in MeOH (10 mL) was added NaBH ₄ (276 mg, 7.3 mmol) in portions at 0℃. Then the mixture was stirred at RT for 1 hour. The mixture was diluted with water (20 mL) and the resulting solution was extracted with EA (15 mL×3) . The combined organic layers were washed with brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated. The resulting residue was purified by silica gel column, eluting with PE/EA= 5/1, to give the title compound (1 g, 99%) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 7.42 (d, J = 8.0 Hz, 1H) , 7.22 (d, J= 8.0 Hz, 1H) , 7.06 (d, J= 8.0 Hz, 1H) , 5.11-5.08 (m, 1H) , 4.72 (d, J= 16.0 Hz, 1H) , 4.53 (d, J= 16.0 Hz, 1H) , 3.63 (br, 2H) , 2.86 (br, 2H) , 1.49 (s, 12H) .

Descriptions 143-150

D143-D150 were prepared using a similar procedure to that described for D 142.

D143: tert-butyl 4- (2- (1-hydroxyethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D144: tert-butyl 3- (2- (1-hydroxyethyl) phenyl) -3-methoxyazetidine-1-carboxylate

D145: 1- (2- (azetidin-1-yl) phenyl) ethanol

D146: tert-butyl 3- (2- (1-hydroxyethyl) phenyl) pyrrolidine-1-carboxylate

D147: tert-butyl 3- (1- (1-hydroxyethyl) cyclopropyl) piperidine-1-carboxylate

D148: tert-butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate

D149 &D150: tert-butyl ( (2R) -8- (1-hydroxyethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate and tert-butyl ( (2S) -8- (1-hydroxyethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate

Descriptions 151-152

tert-butyl (R) -8- (1-acetoxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D151)

tert-butyl (S) -8- (1-hydroxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D152)

To a solution of tert-butyl 8- (1-hydroxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (828 mg, 2.99 mmol) and Novozyme 435 (828 mg, 2.99 mmol) in THF (14 mL) was added isopropenyl acetate (1.624 mL, 14.93 mmol) . The reaction was heated to 50℃ for 72 hrs. The reaction was then cooled to RT and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (PE/EA = 100%to 60%) to give the title compound D151 (467 mg, 48%) and the title compound D152 (403 mg, 47%) . D151: MS (ESI) : C ₁₈H ₂₅NO ₄ requires 319; found 342 [M+Na] ⁺. D152: MS (ESI) : C ₁₆H ₂₃NO ₃ requires 277; found 300 [M+Na] ⁺.

Description 153

(S) -1- (2-bromophenyl) ethanol (D153)

In a 250 mL round-bottomed flask containing THF (30 mL) was added (R) -CBS (0.557 g, 2.010 mmol) followed by the addition of borane-methyl sulfide complex (2M, 11.05 mL, 22.11 mmol) at RT and stirred for 15 min. The reaction mixture was then cooled to 0℃, and to the cooled reaction mixture 1- (2-bromophenyl) ethan-1-one (4 g, 20.10 mmol) in THF (80 mL) was added dropwise over 3 hrs at 0℃ and stirred at RT for another 1 hour. The reaction mixture was quenched with MeOH (40 mL) and stirred for an additional 15 min. Then the reaction mixture was concentrated and purified via flash chromatography (silica gel: 50g+10g, EA=15%in EA and PE) to give the title compound (3.7 g, 92%, ee 86.5%) as a colorless oil. 2 g of the title compound (ee 86.5%) was further purified with trituratation via hexane (1 mL) to give the title compound (1.5 g, 37.1%, ee 94.6%) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (dd, J = 7.82, 1.71 Hz, 1 H) , 7.51 (dd, J= 7.95, 1.35 Hz, 1 H) , 7.31-7.37 (m, 1 H) , 7.12 (td, J= 7.58, 1.71 Hz, 1 H) , 5.24 (qd, J= 6.36, 3.42 Hz, 1 H) , 1.46 -1.51 (m, 3 H) .

Description 154

(R) -1- (2-brom ophenyl) ethanol (D154)

In a 100 mL round-bottomed flask containing (S) -CBS (0.299 mL, 1.005 mmol) in THF (20 mL) was added borane-methyl sulfide complex (5.53 mL, 11.05 mmol) at RT and stirred for 15 min. The reaction mixture was then cooled to 0℃, and to the cooled reaction mixture 1- (2-bromophenyl) ethan-1-one (2 g, 10.05 mmol) in THF (40 mL) was added dropwise over 3 hrs at 0℃ and stirred at RT for another 1 hour. The reaction mixture was quenched with MeOH (20 mL) and stirred for an additional 15 min. Then the reaction mixture was concentrated and purified via silica gel flash chromatography (EA = 15%in EA and PE) to give the title compound (1.7 g, 84 %, ee 91.5%) as a colorless oil. The title compound (ee 91.5%) was further purified with trituratation via hexane (1 mL) to give the title compound (1.2 g, 59 %, ee 99.5%) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (dd, J = 7.83, 1.96 Hz, 1 H) , 7.52 (dd, J = 7.95, 1.34 Hz, 1 H) , 7.32-7.37 (m, 1 H) , 7.13 (td, J= 7.70, 1.71 Hz, 1 H) , 5.25 (qd, J= 6.40, 3.55 Hz, 1 H) , 1.49 (d, J= 6.36 Hz, 3 H)

Description 155

tert-butyl 4- (2- (1-hydroxyethyl) phenyl) piperidine-1-carboxylate (D155)

To a solution of tert-butyl 4- (2- (1-hydroxyethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (1.4 g, 4.62 mmol) in MeOH (20 mL) was added Pd/C (280 mg, wet 10%) and the mixture was stirred at RT under H ₂ (1 atm) for 7 hrs. The mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (PE/EA= 3/1) to give the title compound as colorless oil (960 mg, 68%) . MS (ESI) : C ₁₈H ₂₇NO ₃ requires 305; found 306 [M+H] ⁺.

Description 156

(S) -tert-butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (D156)

To a solution of BH ₃·Me ₂S (10M, 0.23 mL, 2.30 mmoL) in THF (2.3 mL) was added (R) -CBS (1M, 0.17 mL, 0.17 mmol) at RT and then the mixture was reflux for 1 hrs. After the mixture was cooled to RT, tert-butyl 3- (2-acetylphenyl) -3-fluoroazetidine-1-carboxylate (511 mg, 1.74 mmol in THF 5 mL) was added dropwise via syringe pump over 1 hour and stirred at RT overnight. Then 1N HC1 (aq., 6 mL) was added at 0℃, extracted with EA (30 mL) , washed with water (20 mL) and brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (PE/EA = 2/1) to give the title compound (351 mg, 68%, ee 50%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.71 (d, J= 7.5 Hz, 1H) , 7.49-7.44 (m, 1H) , 7.33-7.28 (m, 2H) , 4.97-4.93 (m, 1H) , 4.58-4.34 (m, 4H) , 1.86 (s, 1H) , 1.51 (d, J= 6.0 Hz, 3H) , 1.45 (s, 9H) . The (S) -tert-butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (1.58 g, 5.36 mmol, ee 50%) was purified by chiral HPLC prepare condition: (column: Chiral IE; method: hexane/EtOH= 80/20) to give the title compound (1.10 g, 70%, ee 100%) as a colorless oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.72 (d, J= 7.8 Hz, 1H) , 7.49-7.44 (m, 1H) , 7.33-7.31 (m, 2H) , 4.97-4.94 (m, 1H) , 4.58-4.34 (m, 4H) , 1.89 (s, 1H) , 1.51 (d, J= 6.0 Hz, 3H) , 1.45 (s, 9H) .

Descriptions 156-157

(R) -tert-butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (D157)

tert-Butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (3.1 g, 10.50 mmol) was separated by Chiral HPLC (Column: AD 30*250mm, 5um (Decial) ; Column temperature: 35 ℃; Mobile phase: CO ₂/Methanol (0.2%Methanol Ammonia) = 85/15) to give the title compound D156 (1.4 g, 4.74 mmol, 45.2%) as a colorless oil and the title compound D157 (1.3 g, 4.40 mmol, 41.9%) as a colorless oil. D156: MS (ESI) : C ₁₆H ₂₂FNO ₃ requires 295; found 222 [M-56-18+H] ⁺. Chiral-HPLC: rt = 4.76 min. D157: MS (ESI) : C ₁₆H ₂₂FNO ₃ requires295; found 222 [M-56-18+H] ⁺. Chiral-HPLC: rt = 8.19 min.

Description 158

(S) -tert-butyl 3-fluoro-3- (2- (1- ( (methylsulfonyl) oxy) ethyl) phenyl) azetidine-1-carboxylate (D158)

To a solution of (S) -tert-butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (137 mg, 0.46 mmol) in DCM (5 mL) was added TEA (139 mg, 0.71mmol) at 0℃. Then the mixture was stirred at 0℃ for 0.5 hrs. The mixture was diluted with H ₂O (5 mL) and extracted with DCM (5 mL ×3) . The organic layers were dried over Na ₂SO ₄, filtered and concentrated to give the crude title compound (171 mg, 100%) as a yellow oil. ¹H NMR (300 MHz, CDCl ₃) : δ 7.67 (d, J= 7.8 Hz, 1H) , 7.51 (t, J = 6.9 Hz, 1H) , 7.43-7.34 (m, 2H) , 5.83-5.80 (m, 1H) , 4.62-4.33 (m, 4H) , 2.83 (s, 3H) , 1.69 (d, J= 6.3 Hz, 3H) , 1.46 (s, 9H) .

Description 159

D159 was prepared using a similar procedure to that described for D158.

D159: (R) -tert-butyl 3-fluoro-3- (2- (1- ( (methylsulfonyl) oxy) ethyl) phenyl) azetidine-1-carboxylate

Description 160

(R) -tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate (D160)

To a solution of N- (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (200 mg, 0.43 mmol) , (S) -tert-butyl 3-fluoro-3- (2- (1-hydroxyethyl) phenyl) azetidine-1-carboxylate (127 mg, 0.43 mmol) and PPh ₃ (225 mg, 0.86 mmol) in THF (3 mL) , cooled by ice-salt bath , was added DEAD (174 mg, 0.86 mmol) dropwise, then the mixture was stirred at RT overnight. The reaction solution was concentrated and the residue was purified by colum chromatography on silica gel (EA/PE = 0%to 50%) to give the title compound (80 mg, 25%) as a white solid. MS (ESI) : C ₃₅H ₃₆F ₂N ₄O ₈S ₂ requires 742; found 743 [M+H] ⁺.

Description 161

(R) -tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate (D161)

To a solution of N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (463 mg, 1.0 mmol) and (S) -tert-butyl 3-fluoro-3- (2- (1- ( (methylsulfonyl) oxy) ethyl) phenyl) azetidine-1-carboxylate (464 mg, 1.24 mmol) in 1, 4-dioxane/H ₂O (3 mL/1 mL) was added K ₂CO ₃ (276 mg, 2.0 mmol) at RT. The mixture was stirred at 80℃ for 16 hrs. The mixture was concentrated and purified by column chromatograph on silica gel eluting with PE/EA= 5/1, to give the title compound (58 mg, 1%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.76-7.73 (m, 1H) , 7.46-7.40 (m, 6H) , 7.14-7.06 (m, 2H) , 6.35-6.33 (m, 2H) , 5.79-5.73 (m, 1H) , 5.02 (s, 2H) , 4.58-4.30 (m, 4H) , 3.75 (s, 3H) , 3.67 (s, 3H) , 1.95 (s, 3H) , 1.45 (s, 9H) .

Description 162

D162 was prepared using a similar procedure to that described for D161.

D162: (S) -tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate

Description 163

N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D163)

A mixture of 1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethanol (236 mg, 1.00 mmol) and N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (232 mg, 0.500 mmol) in toluene (8 mL) was added CMBP (362 mg, 1.50 mmol) . The resulting mixture was stirred in a sealed tube at 80℃ for 6 hrs. Then the mixture was cooled to RT and concentrated under vacuum. The residue was purified by prep-TLC (PE/EA= 5/2) to give the title compound (50 mg, 7%) as a yellow oil. ¹H NMR (400 MHz, CDCl ₃) : δ 7.68-7.65 (m, 1H) , 7.43-7.34 (m, 6H) , 7.12 (d, J = 8.0 Hz, 1H) , 7.04 (dd, J = 3.6, 1.2 Hz, 1H) , 6.35-6.32 (m, 2H) , 6.03-5.96 (m, 1H) , 4.99 (s, 2H) , 4.76 (dd, J= 33.2, 12.0 Hz, 1H) , 4.59-4.49 (m, 2H) , 3.82-3.67 (m, 4H) , 3.69 (s, 3H) , 3.50-3.46 (m, 1H) , 2.00-1.95 (m, 3H) , 1.61-1.31 (m, 6H) .

Description 164

tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D164)

To a solution of tert-butyl 8- (1-hydroxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (500 mg, 1.81 mmol) and N, N-bis (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (1.06 g, 1.99 mmol) in THF (10 mL) at 0℃ was added PPh ₃ (947 mg, 3.61 mmol) . After the mixture was stirred at 0℃ for 15 min DIAD (1.9 mol/L in toluene, 1.9 mL, 3.61 mmol) was added dropwise at 0℃. The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column on C18 (ACN/H ₂O = 30-60%) to give the title compound (500 mg, 35%) as a white solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.50-7.40 (m, 1H) , 7.22-7.13 (m, 6H) , 6.39-6.37 (m, 2H) , 6.22-6.17 (m, 2H) , 5.79-5.71 (m, 1H) , 4.89-4.72 (m, 1H) , 4.38 (s, 4H) , 4.31-4.19 (m, 1H) , 3.77 (s, 6H) , 3.72-3.65 (m, 1H) , 3.61 (s, 6H) , 3.56-3.41 (m, 1H) , 2.96-2.79 (m, 2H) , 1.94 (d, J= 7.2 Hz, 3H) , 1.48 (s, 9H) .

Description 165

tert-butyl 8- (1- (6- (N, N-bis (2, 4-dim etho xybenzyl) sulfam o yl) -7-fluoro-2-o x obenzo [d] o xazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D165)

To a solution of tert-butyl 8- (1-hydroxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (1.10 g, 3.97 mmol) and N, N-bis (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (2.32 g, 4.37 mmol) in dry THF (20 mL) at 0℃ was added PPh ₃ (2.08 g, 7.94 mmol) . After the mixture was stirred at 0℃ for 15 min, DIAD (1.9 mol/L in toluene, 4.2 mL, 7.9 mmol) was added dropwise to the reaction mixture at 0℃. Then the reaction mixture was warmed to RT and stirred for 3.5 hrs. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE/EA= 3/1) to give the title compound (1.8 g, 57%) as a white solid. MS (ESI) : C ₄₁H ₄₆FN ₃O ₁₀S requires 791; found 792 [M+H] ⁺.

Description 166

tert-butyl 8- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D166)

To a solution of tert-butyl 8- (1-hydroxyethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (60 mg, 0.215 mmol) , N- (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (100 mg, 0.215 mmol) and Ph ₃P (113 mg, 0.430 mmol) in THF (5 mL) was added dropwise DIAD (87 mg, 0.43 mmol, in 2 mL THF) at 0℃ under N ₂. The reaction mixture was stirred at RT for 3 hrs. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×2) . The combined organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (60 mg, yield 38.5%) as a yellow oil. MS (ESI) : C ₃₅H ₃₇FN ₄O ₈S ₂ requires 724; found 725 [M+H] ⁺.

Descriptions 167-221

D167-D221 were prepared using a similar procedure to that described for D 166.

D167: tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D168: tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D169: 3- (1- (2- (azetidin-1-yl) phenyl) ethyl) -N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D170: 3- (1- (2- (azetidin-1-yl) phenyl) ethyl) -N- (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D171: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-methoxyazetidine-1-carboxylate

D172: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-methoxyazetidine-1-carboxylate

D173: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) azetidine-1-carboxylate

D174: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) azetidine-1-carboxylate

D175: tert-butyl 2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -6-methylbenzylcarbamate

D176: tert-butyl 2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -6-methylbenzylcarbamate

D177: tert-butyl 2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) benzylcarbamate

D178: tert-butyl 2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) benzylcarbamate

D179: tert-butyl 8- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate

D180: tert-butyl 8- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate

D181: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) pyrrolidine-1-carboxylate

D182: tert-butyl (2- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl ) sulfamo yl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -2, 2-difluoroethyl) carbamate

D183: tert-butyl (2- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -2, 2-difluoroethyl) carbamate

D184: tert-butyl 2, 4-dimethoxybenzyl (3- (1- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) propyl) carbamate

D185: tert-butyl 4- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) piperidine-1-carboxylate

D186: tert-butyl 4- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) piperidine-1-carboxylate

D187: tert-butyl 3- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) piperidine-1-carboxylate

D188: tert-butyl 3- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) piperidine-1-carboxylate

D189: tert-butyl 2- (1- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) piperidine-1-carboxylate

D190: tert-butyl 2- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) piperidine-1-carboxylate

D191: tert-butyl 2, 4-dimethoxybenzyl (3- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) propyl) carbamate

D192: tert-butyl 2, 4-dimethoxybenzyl (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -6-fluorophenethyl) carbamate

D193: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (5-fluoropyridin-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate

D194: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate

D195: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (isoxazol-3-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate

D196: tert-butyl 3- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate

D197: tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

D198: tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

D199: tert-butyl 3- ( (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) methyl) piperidine-1-carboxylate

D200: tert-butyl 2- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) -6-methylbenzylcarbamate

D201: tert-butyl (2-amino-2-oxoethyl) (2- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) -6-methylbenzyl) carbamate

D202: tert-butyl 4- ( (1- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) methyl) piperidine-1-carboxylate

D203: tert-butyl 2, 4-dimethoxybenzyl (2- (1- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) ethyl) carbamate

D204: tert-butyl 2, 4-dimethoxybenzyl (2- (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) ethyl) carbamate

D205: tert-butyl 2, 4-dimethoxybenzyl (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenethyl) carbamate

D206: tert-butyl (8- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate

D207: N- (2, 4-dimethoxybenzyl) -4-fluoro-3- (1- (2-iodophenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D208: N- (2, 4-dimethoxybenzyl) -7-fluoro-3- (1- (2-iodophenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D209: tert-butyl 3- (2- (1- (6- (benzylthio) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate

D210: tert-butyl 4- ( (1- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) cyclopropyl) methyl) piperidine-1-carboxylate

D211: tert-butyl 4- (2- (1- (6- (benzylthio) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D212: tert-butyl 4- (2- (1- (6- (benzylthio) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D213: 3- (1- (7- ( (tert-butyldimethylsilyl) oxy) -5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D214: tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D215: tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D216: tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D217: N, N-bis (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D218: tert-butyl ( (2S/2R) -8- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate

D219: tert-butyl ( (2S/2R) -8- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate

D220: tert-butyl 4- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate

D221: tert-butyl 3- ( (1- ( (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) methyl) piperidine-1-carboxylate

Descriptions 222-223

tert-butyl ( (R/S) -8- ( (R) -1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate &tert-butyl ( (R/S) -8- ( (S) -1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (D222 &D223)

To a solution of N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (100 mg, 0.22 mmol) , tert-butyl ( (2R/S) -8- (1-hydroxyethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (64 mg, 0.22 mmol) (isomer 1) and PPh ₃ (116 mg, 0.44 mmol) in THF (2 mL) was added DIAD (89 mg, 0.44 mmol, in 0.5 mL THF) under N ₂ at 0℃. The reaction mixture was stirred at RT overnight. The mixture was added H ₂O (10 mL) and extracted with EA (10 mL ×3) . The combined organic phase was washed with brine (10 mL ×3) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by chiral column (Chiralcel OD-H, 250mm*4.6mm, 5um, Mobile phase: Hex∶EtOH = 60∶40) to give the title compounds (60 mg and 66 mg, ) as white solid. Isomer 1: HPLC (Chiralcel OD-H, 250 mm*4.6 mm, 5 um, Mobile Phase: Hex∶EtOH = 60∶40, rt = 6.643 min; MS (ESI) : C ₃₆H ₃₉FN ₄O ₈S ₂ requires 738; found 739 [M+H] ⁺. Isomer 2: HPLC (Chiralcel OD-H, 250 mm*4.6 mm, 5 um, Mobile Phase: Hex∶EtOH = 60∶40, rt = 8.615 min; MS (ESI) : C ₃₆H ₃₉FN ₄O ₈S ₂ requires 738; found 739 [M+H] ⁺.

Descriptions 224-225

D224 &D225 were prepared using a similar procedure to that described for D222 &D223, with the specified chiral column as listed in the table.

D224 &D225: tert-butyl ( (R/S) -8- ( (R) -1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate &tert-butyl ( (R/S) -8- ( (S) -1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate

Description 226

(R) -3- (1- (2-bromophenyl) ethyl) -N, N-bis (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D226)

To a solution of PPh ₃ (1045 mg, 3.98 mmol) in THF (2 mL) , DIAD (803.2 mg, 3.97 mmol) solution in anhydrous THF (1 mL) was added dropwise at 0℃ under N ₂. The reaction mixture was stirred for 10 min at 0℃, white precipitate formed gradually. A mixed solution of (S) -1- (2-bromophenyl) ethan-1-ol (409.7 mg, 2.038 mmol) and N, N-bis (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (1026.4 mg, 1.927 mmol) in anhydrous THF (8.5 mL) was added dropwise at 0 ℃ under N ₂. The reaction mixture was stirred overnight. Temperature was gradually warmed to RT. Solvent was removed under vacuum. The residue was divided into 3 parts, each was purified with C18 reverse phase chromatography (ACN/water with 0.05%TFA, ACN%= 55%-100%) . Desired fractions were collected and neutralized with saturated NaHCO ₃ solution. Most ACN was removed by rotavap. The aqueous layer was extracted with EA twice (2×80 mL) . Combined organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness, freeze-dried, to give the title compound (941 mg, 64.5 %) as a white solid. ¹H NMR (400 MHz, CDCl ₃) 7.68 (dd, J= 1.7, 7.8 Hz, 1H) , 7.61 (dd, J= 1.2, 8.1 Hz, 1H) , 7.45 (dt, J= 1.1, 7.8 Hz, 1H) , 7.36-7.27 (m, 2H) , 7.10 (d, J = 8.3 Hz, 2H) , 6.33 (dd, J= 2.3, 8.4 Hz, 2H) , 6.27 (d, J= 8.6 Hz, 1H) , 6.19 (d, J= 2.4 Hz, 2H) , 5.67 (q, J= 7.2 Hz, 1H) , 4.45 (s, 4H) , 3.75 (s, 6H) , 3.59 (s, 6H) , 1.93 (d, J = 7.1 Hz, 3H) . MS (ESI) : C ₃₃H ₃₂BrFN ₂O ₈S requires 714; found 737 [M+Na] ⁺.

Descriptions 227-228

D227 &D228 were prepared using a similar procedure to that described for D226.

D227: (R) -3- (1- (2-bromophenyl) ethyl) -N, N-bis (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

D228: (S) -3- (1- (2-bromophen yl ) ethyl ) -N, N-b is (2, 4-dimetho xybenzyl ) -7-fluoro-2-o x o-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

Description 229

(R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D229)

The mixture of (R) -3- (1- (2-bromophenyl) ethyl) -N, N-bis (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (475 mg, 0.664 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (308.7 mg, 0.998 mmol) and potassium carbonate (183 mg, 1.328 mmol) in 1, 4-dioxane (9 mL) and water (1.8 mL) was bubbled with N ₂ for 2 min, then PdCl ₂ (dppf) -CH ₂Cl ₂ adduct (54.2 mg, 0.066 mmol) was added. The reaction mixture was heated at 100 ℃ by microwave for 1 h. The mixture of (R) -3- (1- (2-bromophenyl) ethyl) -N, N-bis (2, 4-dimethoxybenzyl) -7-fluoro-2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (460 mg, 0.643 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (296 mg, 0.957 mmol) and potassium carbonate (178 mg, 1.286 mmol) in 1, 4-dioxane (9 mL) and water (1.8 mL) was bubbled with N ₂ for 2 min, then PdCl ₂ (dppf) -CH ₂Cl ₂ adduct (52.5 mg, 0.064 mmol) was added. The reaction mixture was heated at 100 ℃ by microwave for 1 h. The two batches were combined. Most solvent was removed under vacuum. The residue was dissolved with EA (50 mL) and water (15 mL) , extracted. The aqueous layer was extracted with EA (30 mL) again. Combined organic layer was concentrated to dryness. The residue was purified with silica gel column chromatography (PE/EA, EA%= 10-35%) . Desired fractions were collected and concentrated to dryness, freeze-dried, to give the title compound (961 mg, 89.9%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.62 (d, J= 7.3 Hz, 1H) , 7.43-7.32 (m, 2H) , 7.20 (dd, J= 6.2, 8.4 Hz, 1H) , 7.11 (d, J= 8.3 Hz, 2H) , 7.08 (dd, J= 1.7, 7.1 Hz, 1H) , 6.32 (dd, J= 2.3, 8.4 Hz, 2H) , 6.19 (d, J= 2.4 Hz, 2H) , 6.07 (d, J= 8.3 Hz, 1H) , 5.81-5.71 (m, 1H) , 5.41-5.14 (m, 1H) , 4.51-4.38 (m, 4H) , 4.07-3.83 (m, 2H) , 3.75 (s, 6H) , 3.68-3.58 (m, 7H) , 3.56-3.45 (m, 1H) , 2.45-2.23 (m, 1H) , 1.94-1.75 (m, 4H) , 1.53-1.48 (m, 9H) . MS (ESI) : C ₄₃H ₄₈FN ₃O ₁₀S requires 817; found 840 [M+Na] ⁺.

Descriptions 230-231

D230 &D231 were prepared using a similar procedure to that described for D229.

D230: (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate,

D231: (S) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Description 232

(R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate (D232)

To a solution of (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (440 mg, 0.538 mmol) in EtOH (18 mL) , Pd/C (10%w/w, 386 mg, 0.163 mmol) was added. The mixture was stirred overnight at RT under H ₂. Filtered, Pd/C was rinsed with EtOH and EA. The combined filtrate was concentrated to dryness, giving the crude product as a pale yellow foaming solid. To a solution of (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (519 mg, 0.635 mmol) in EtOH (25 mL) and EA (4 mL) , Pd/C (10%w/w, 477 mg, 0.202 mmol) was added. The mixture was stirred overnight at RT under H ₂. Filtered, Pd/C was rinsed with DCM several times. The combined filtrate was concentrated to dryness, giving the crude product as a pale yellow foaming solid. Two batches of the crude product were dissolved in EA and combined together. Solvent was removed under vacuum, to give the title compound (755 mg, 78%) as a pale yellow foaming solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.61 (dd, J = 1.7, 7.6 Hz, 1H) , 7.42-7.31 (m, 2H) , 7.30-7.26 (m, 1H) , 7.20 (dd, J= 6.2, 8.4 Hz, 1H) , 7.11 (d, J= 8.3 Hz, 2H) , 6.32 (dd, J= 2.4, 8.3 Hz, 2H) , 6.21 (d, J= 9.3 Hz, 1H) , 6.17 (d, J= 2.4 Hz, 2H) , 5.90 (q, J= 7.1 Hz, 1H) , 4.52-4.37 (m, 4H) , 4.34-4.00 (m, 2H) , 3.75 (s, 6H) , 3.60 (s, 6H) , 2.93-2.78 (m, 2H) , 2.76-2.63 (m, 1H) , 1.89 (d, J=7.1 Hz, 3H) , 1.69 (brs, 2H) , 1.49-1.42 (m, 10H) , 0.93-0.78 (m, 1H) . MS (ESI) : C ₄₃H ₅₀FN ₃O ₁₀S requires 819; found 842 [M+Na] ⁺.

Descriptions 233-234

D233 &D234 were prepared using a similar procedure to that described for D232.

D233: (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H4) -yl) ethyl) phenyl) piperidine-1-carboxylate

D234: (S) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

Description 235

N- (2, 4-dimethoxybenzyl) -3- (1- (2- ( (dimethylamino) methyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D235)

A mixture of N- (2, 4-dimethoxybenzyl) -4-fluoro-3- (1- (2-iodophenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (86 mg, 0.12 mmol) , Potassium dimethylaminomethyltrifluoroboronate (41 mg, 0.23 mmol) , Cs ₂CO ₃ (117 mg, 0.36 mmol) , butyldi-1-adamantylphos (9 mg, 0.024 mmol) and Pd (OAC) ₂ (2.7 mg, 0.012 mmol) in 1, 4-dioxane (2 mL) and H ₂O (0.4 mL) was stirred at 90℃ under N ₂ overnight. The mixture was filtered and washed with EA. The filtrate was diluted with H ₂O (10 mL) and extracted with EA (5 mL×3) . The combined organic layer was washed with brine (5 mL×3) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by pre-TLC to give the title compound (30 mg, 39%) as a yellow solid. MS (ESI) : C ₃₀H ₃₁FN ₄O ₆S ₂ requires 626; found 627 [M+H] ⁺.

Description 236

D236 was prepared using a similar procedure to that described for D235.

D236: N- (2, 4-dimethoxybenzyl) -3- (1- (2- ( (dimethylamino) methyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide

Description 237

tert-butyl 3- (2- (1- (6- (chlorosulfonyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate (D237)

To a mixture of tert-butyl 3- (2- (1- (6- (benzylthio) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate (1.56 g, 2.83 mmol) in AcOH/H2O (15 mL/5 mL) was added NCS (1.51 g, 11.3 mmol) in portions at 0℃ under N ₂. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was extracted with DCM (20 mL ×3) . The combined organic layers were washed with sat. NaHCO ₃ (20 mL×2) , brine (20 mL) and concentrated. The residue was purified by Prep-HPLC to give the title compound (800 mg, 51.8%) as an orange solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.81 (d, J= 7.2 Hz, 1H) , 7.72-7.69 (m, 2H) , 7.51-7.40 (m, 3H) , 5.85 (q, J= 7.2 Hz, 1H) , 4.64-4.49 (m, 2H) , 4.44-4.27 (m, 2H) , 1.98 (d, J = 7.2 Hz, 3H) , 1.46 (s, 9H) .

Description 238

tert-butyl 4- (2- (1- (6- (chlorosulfonyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D238)

To a solution of tert-butyl 4- (2- (1- (6- (benzylthio) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (450 mg, 0.8 mmol) in ACN/AcOH/H ₂O (20 mL/2.25 mL/6.75 mL) was added 1, 3-dichloro-5, 5-dimethyl-imidazoline-2, 4-dione (317 mg, 1.6 mmol) in ACN (2.5 mL) dropwise at -10℃ under N ₂. After addition, the mixture was stirred the same temperature for 5 min. Then the reaction solution was diluted with ice-water (25 mL) and the resulting solution was extracted with Et ₂O (25 mL×3) . The combined organic layer was washed with brine (50 mL) and concentrated. The residue was purified by Prep-HPLC to afford the title compound in H ₂O/ACN (5 mL/15 mL) , which was used for the next reaction without concentration. MS (ESI) : C ₂₅H ₂₆ClFN ₂O ₆S requires 536; found 537 [M+H] ⁺.

Description 239

tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D239)

To a solution of tert-butyl 4- (2- (1- (6- (chlorosulfonyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate in H ₂O/ACN (5 mL/15 mL) was added NH ₃·H ₂O (10 mL) at 0℃ and the mixture was stirred at RT for 30 min. The reaction solution was diluted with H ₂O (30 mL) and the resulting solution was extracted with EA (30 mL×3) . The combined organic layers were washed with brine (50 mL) and concentrated. The residue was purified by Prep-HPLC to afford the title compound (157 mg, 38%for above two steps) as a white solid. MS (ESI) : C ₂₅H ₂₈FN ₃O ₆S requires 517; found 518 [M+H] ⁺.

Description 240

tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D240)

To a solution of tert-butyl 4- (2- (1- (6- (benzylthio) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (200 mg, 0.357 mmol) in ACN/AcOH/H2O (17 mL/2.0 mL/6.0 mL) was added a solution of 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (176 mg, 0.89 mmol) in ACN (3.0 mL) dropwise at -10℃. After addition, the mixture was stirred at the same temperature for 5 min. NH ₃·H ₂O (10 mL) was added into above solution dropwise at the same temperature. Then the mixture was stirred at RT for 30 min. The reaction solution was poured into ice-water (50 mL) and the resulting mixture was extracted with EA (50 mL ×2) . The combined organic layer was washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was combined with the below batch.

To a solution of tert-butyl 4- (2- (1- (6- (benzylthio) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (700 mg, 1.25 mmol) in ACN/AcOH/H ₂O (34 mL/4.0 mL/12.0 mL) was added a solution of 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (615.6 mg, 3.125 mmol) in ACN (3.0 mL) dropwise at -10℃. After addition, the mixture was stirred at the same temperature for 5 min. NH ₃·H ₂O (20 mL) was added into above solution dropwise at the same temperature. Then the mixture was stirred at RT for 30 min. The reaction solution was poured into ice-water (100 mL) and the resulting mixture was extracted with EA (50 mL ×2) . The combined organic layer was washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue together with the former batch was purified by Prep-HPLC to give the title compound (450 mg, 54%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.67 (d, J= 7.6 Hz, 1H) , 7.52 (t, J= 6.8 Hz, 1H) , 7.43-7.34 (m, 2H) , 7.07 (d, J= 8.0 Hz, 1H) , 6.42-6.25 (m, 1H) , 5.60-5.84 (m, 1H) , 5.27-5.20 (m, 3H) , 4.02-3.75 (m, 2H) , 3.70-3.40 (m, 2H) , 2.37-2.32 (m, 1H) , 1.88-1.80 (m, 4H) , 1.50 (s, 9H) .

Description 241

4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D241)

To a solution of N, N-bis (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (1.45g, 1.94 mmol) in DCM (40 mL) was added TFA (4 mL) . Then the mixture was stirred at RT for 24 hrs. The mixture was concentrated and the residue was purified by column chromatography C18 (ACN/H ₂O, from 5%to 60%) to give the title compound (388 mg, 54%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d ₆) : δ 7.59 (s, 1H) , 7.55-7.52 (m, 1H) , 7.49-7.45 (m, 3H) , 7.41-7.36 (m, 1H) , 7.35-7.31 (m, 2H) , 5.91-5.84 (m, 1H) , 4.53 (d, J= 12.9 Hz, 1H) , 4.39 (d, J= 13.5 Hz, 1H) , 1.86 (d, J= 7.2 Hz, 3H) .

Description 242

4-fluoro-3- (1- (2-formylphenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D242)

To a solution of 4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (349 mg, 0.950 mmol) in DCM (30 mL) was added Dess-Martin periodinane (600 mg, 1.43 mmol) at 0-5℃. Then the mixture was stirred at 0-5℃ for 3 hrs. The mixture was partitioned with Na ₂S ₂O ₅ (sat., 70 mL) and DCM (30 mL) . The aqueous layer was extracted with DCM (30 mL×2) . The combined organic layer was washed with brine (50 mL×2) , dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (PE/EA= 4/1) to give the title compound (263 mg, 76%) as a white solid. ¹H NMR (300 MHz, CDCl ₃) : δ 10.09 (s, 1H) , 7.85 (dd, J= 7.2, 1.5 Hz, 1H) , 7.73 (d, J= 7.8 Hz, 1H) , 7.67 (t, J= 8.4 Hz, 1H) , 7.62-7.53 (m, 3H) , 6.70-6.62 (m, 1H) , 4.91 (s, 2H) , 2.00 (d, J= 7.2 Hz, 3H) .

Description 243

4-fluoro-3- (1- (2- (morpholinomethyl) phenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D243)

To a solution of 4-fluoro-3- (1- (2-formylphenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (100 mg, 0.274 mmol) and morpholine (119 mg, 1.37 mmol) in DCE (24 mL) was added acetic acid (9 drops) . Then the mixture was stirred at 0-5℃ for 10 min. To this mixture was added NaBH (OAc) ₃ (290 mg, 1.37 mmol) . The resulting mixture was stirred at RT overnight. The mixture was poured into water (50 mL) . DCM (50 mL) was added to extract the title compound. The organic layer was washed with brine (50 mL) , dried over Na ₂SO ₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (5-30%EA in PE) to give the title compound (68 mg, 57%) as a white solid. ¹H NMR (300 MHz, DMSO-d ₆) : δ 7.66-7.63 (m, 2H) , 7.47-7.44 (m, 3H) , 7.38 (t, J= 7.2 Hz, 1H) , 7.30 (t, J= 7.2 Hz, 1H) , 7.23 (dd, J = 7.2, 1.6 Hz, 1H) , 6.00-5.97 (m, 1H) , 3.65 (d, J = 12.0 Hz, 1H) , 3.28-3.21 (m, 3H) , 3.16-3.07 (m, 2H) , 2.20-2.15 (m, 2H) , 2.03-1.97 (m, 2H) , 1.85 (d, J= 7.2 Hz, 3H) .

Description 244

4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D244)

To a mixture of 4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (475 mg, 1.29 mmol) , 3, 4-dihydro-2H-pyran (163 mg, 1.94 mmol) and MgSO ₄ (1.0 g) in CH ₂Cl ₂ (30 mL) was added pyridine 4-methylbenzenesulfonate (65 mg, 0.26 mmol) . The resulting mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography C18 (ACN/H2O= 5-60%) to give the title compound (320 mg, 55%) as a white solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.71-7.65 (m, 1H) , 7.56 (s, 1H) , 7.49 (dd, J= 9.9, 1.2 Hz, 1H) , 7.41-7.31 (m, 3H) , 6.07-5.97 (m, 1H) , 4.83-4.70 (m, 1H) , 4.62-4.52 (m, 2H) , 3.86-3.72 (m, 1H) , 3.54-3.45 (m, 1H) , 1.98 (d, J= 6.3 Hz, 3H) , 1.55-1.40 (m, 6H) .

Descriptions 245-246

(R) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimetho xybenzyl) -N- (thiazol-2-yl) sulfamo yl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate & (S) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2- oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D 245 &D246)

tert-Butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (1.15 g, 1.53 mmol) was separated by chiral column (Chiralpak IC, 5 um, 4.6*250mm, Phase: Hex∶EtOH = 60∶40) to give the title compounds (198 mg and 215 mg) as white foam. Isomer 1: Chiral HPLC: rt = 12.69 min; ＞99%ee; ¹H NMR (400 MHz, CDCl ₃) : δ 7.64-7.60 (m, 1H) , 7.44-7.42 (m, 2H) , 7.32-7.27 (m, 3H) , 7.12 (d, J= 8.4 Hz, 1H) , 7.07-7.03 (m, 2H) , 6.36-6.32 (m, 2H) , 5.88 (q, J= 6.8 Hz, 1H) , 5.33-5.23 (m, 1H) , 4.99 (s, 2H) , 3.97-3.87 (m, 2H) , 3.75 (s, 3H) , 3.69 (s, 3H) , 3.65-3.55 (m, 1H) , 3.50-3.40 (m, 1H) , 2.42-2.32 (m, 1H) , 1.98-1.91 (m, 1H) , 1.89 (d, J= 6.8 Hz, 3H) , 1.50 (s, 9H) . Isomer 2: Chiral HPLC: rt = 13.99 min; ＞97%ee; ¹H NMR (400 MHz, CDCl ₃) : δ 7.64-7.60 (m, 1H) , 7.44-7.42 (m, 2H) , 7.32-7.27 (m, 3H) , 7.12 (d, J= 8.4 Hz, 1H) , 7.07-7.03 (m, 2H) , 6.36-6.32 (m, 2H) , 5.88 (q, J= 6.8 Hz, 1H) , 5.33-5.23 (m, 1H) , 4.99 (s, 2H) , 3.97-3.87 (m, 2H) , 3.75 (s, 3H) , 3.69 (s, 3H) , 3.65-3.55 (m, 1H) , 3.50-3.40 (m, 1H) , 2.42-2.32 (m, 1H) , 1.98-1.91 (m, 1H) , 1.89 (d, J= 6.8 Hz, 3H) , 1.50 (s, 9H) .

Descriptions 247-254

D247-D254 were prepared using a similar procedure to that described for D245 &D246, with the specified chiral column as listed in the table.

D247 &D248: (R) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate and (S) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D249 &D250: (R) -tert-butyl 4- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate and (S) -tert-butyl 4- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate

D251 &D252: (R) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate and (S) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

D253 &D254: (R) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate and (S) -tert-butyl 4- (2- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Descriptions 255-256

(R) -tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D255)

(S) -tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-o xobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D256)

The compound tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (720 mg, 0.910 mmol) was separated by chiral HPLC under the condition (chiralpak IB; phase: Hex∶EtOH = 80∶20) to give the title compound D255 (272 mg, 38%) and the title compound D256 (265 mg, 37%) both as white solid. D255: ¹H NMR (400 MHz, CDCl ₃) : δ 7.49-7.40 (m, 1H) , 7.25-7.13 (m, 6H) , 6.39-6.37 (m, 2H) , 6.20-6.19 (m, 2H) , 5.79-5.71 (m, 1H) , 4.84-4.76 (m, 1H) , 4.38 (s, 4H) , 4.31-4.22 (m, 1H) , 3.77 (s, 6H) , 3.74-3.66 (m, 1H) , 3.61 (s, 6H) , 3.58-3.53 (m, 1H) , 2.95-2.81 (m, 2H) , 1.95 (d, J = 6.8 Hz, 3H) , 1.48 (s, 9H) . Chiral HPLC: rt = 11.349 min, 100%ee; D256: ¹H NMR (400 MHz, CDCl ₃) : δ 7.48-7.42 (m, 1H) , 7.24-7.13 (m, 6H) , 6.39-6.37 (m, 2H) , 6.20-6.19 (m, 2H) , 5.78-5.71 (m, 1H) , 4.87-4.75 (m, 1H) , 4.38 (s, 4H) , 4.30-4.21 (m, 1H) , 3.77 (s, 6H) , 3.75-3.66 (m, 1H) , 3.61 (s, 6H) , 3.58-3.52 (m, 1H) , 2.94-2.79 (m, 2H) , 1.95 (d, J = 7.2 Hz, 3H) , 1.48 (s, 9H) . Chiral HPLC: rt = 13.159 min, 99%ee.

Descriptions 257-258

(R) -tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D257)

(S) -tert-butyl 8- (1- (6- (N, N-bis (2, 4-dim etho xybenzyl) sulf a m o yl) -7-fluo ro-2-o x obenzo [d] o xazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D258)

The racemic compound tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (1.80 g, 2.28 mmol) was separated by chiral HPLC under the condition (chiralpak IB; phase: Hex∶ EtOH = 60∶40) to give the title compound D257 (740 mg, 41%) and the title compound D258 (760 mg, 42%) both as white solid. D257: ¹H NMR (400 MHz, CDCl ₃) : δ 7.53-7.45 (m, 1H) , 7.34-7.30 (m, 1H) , 7.25-7.19 (m, 2H) , 7.11 (d, J= 8.4 Hz, 2H) , 6.32 (d, J= 10.4 Hz, 2H) , 6.26-6.17 (m, 3H) , 5.67-5.62 (m, 1H) , 4.78-4.69 (m, 1H) , 4.49-4.40 (m, 4H) , 4.11-4.02 (m, 1H) , 3.75 (s, 6H) , 3.71-3.65 (m, 1H) , 3.60 (s, 6H) , 3.58-3.51 (m, 1H) , 2.93-2.80 (m, 2H) , 1.89 (d, J= 6.4 Hz, 3H) , 1.48 (s, 9H) . Chiral HPLC: rt = 7.712 min, 100%ee. D258: ¹H NMR (400 MHz, CDCl ₃) : δ 7.52-7.45 (m, 1H) , 7.35-7.29 (m, 1H) , 7.23-7.17 (m, 2H) , 7.11 (d, J= 8.0 Hz, 2H) , 6.32 (d, J= 10.8 Hz, 2H) , 6.25-6.18 (m, 3H) , 5.67-5.62 (m, 1H) , 4.78-4.69 (m, 1H) , 4.49-4.40 (m, 4H) , 4.10-4.01 (m, 1H) , 3.75 (s, 6H) , 3.70-3.64 (m, 1H) , 3.60 (s, 6H) , 3.57-3.52 (m, 1H) , 2.92-2.80 (m, 2H) , 1.89 (d, J= 7.2 Hz, 3H) , 1.48 (s, 9H) . Chiral HPLC: rt = 10.757 min, 99.5%ee.

Descriptions 259, 230, 229, 231

D259, D230, D229, D231 were prepared using a similar procedure to that described for Description 245-246, with the specified chiral column as listed in the table.

D259: (S) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D230: (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D229: (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Description 260

(R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt (D260)

To a solution of (R) -tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (242 mg, 0.306 mmol) in DCM (5 mL) was added TFA (0.5 mL) at RT. The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in methanol (20 mL) and the mixture was filtered. The filtrate was concentrated to give the title compound (150 mg, 100%) as a yellow solid which was used for next step directly.

MS (ESI) : C ₁₈H ₁₈FN ₃O ₄S requires 391; found 392 [M+H] ⁺.

Description 261

(R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt (D261)

To a solution of (R) -tert-butyl 8- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (710 mg, 0.898 mmol) in DCM (3 mL) was added TFA (0.5 mL) at RT. The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in methanol (10 mL) . The mixture was filtered and the filtrate was concentrated to give the title compound (442 mg, 100%) as a yellow solid which was used for next step directly.

MS (ESI) : C ₁₈H ₁₈FN ₃O ₄S requires 391; found 392 [M+H] ⁺.

Description 262

D262 was prepared using a similar procedure to that described for D261.

D262: (S) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt

Descriptions 263

(R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt (D263)

To a mixture of (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-l (2H) -carboxylate (856 mg, 1.05 mmol) in CH ₂Cl ₂ (100 mL) was added TFA (1 mL) at 0℃. Then the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in methanol (50 mL) . The mixture was filtered and the filtrate was concentrated to give the title compound (543 mg, yield 100%) as a yellow solid. MS (ESI) : C ₂₀H ₂₀FN ₃O ₄S requires 417; found 418 [M+H] ⁺.

Descriptions 264-269

D264-D296 were prepared using a similar procedure to that described for D263.

D264: (S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt

D265: (R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt

D266: (S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt

D267 &D268: (R) -7-fluoro-3- (1- (isoindolin-4-yl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt and (S) -7-fluoro-3- (1- (isoindolin-4-yl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt

D269: 7-fluoro-2-oxo-3- ( (1- (piperidin-3-ylmethyl) cyclopropyl) methyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt

Description 270

(R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D270)

To a solution of (R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt (150 mg, 0.304 mmol) in DCM (10 mL) was added TEA (154 mg, 1.52 mmol) at RT. After the mixture was stirred at RT for 15 min, Boc ₂O (131 mg, 0.608 mmol) was added. The reaction mixture was stirred at RT for 3 hrs. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (PE/EA = 1/1) to give the title compound (110 mg, 73%) as a white solid. MS (ESI) : C ₂₃H ₂₆FN ₃O ₆S requires 491; found 392 [M-100+H] ⁺.

Description 271

(R) -tert-butyl 8- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D271)

To a solution of (R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, trifluoroacetic acid salt (424 mg of crude) in DCM (15 mL) was added TEA (435 mg, 4.30 mmol) at RT. After the mixture was stirred at RT for 15 min, Boc ₂O (372 mg, 1.72 mmol) was added. After stirred at RT for 3 hrs the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EA= 1/1) to give the title compound (410 mg, 93%) as a white solid. MS (ESI) : C ₂₃H ₂₆FN ₃O ₆S requires 491; found 392 [M-100+H] ⁺.

Description 272

D272 was prepared using a similar procedure to that described for D271.

D272: (S) -tert-butyl 8- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate

Descriptions 273

(R) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D273)

To a solution of (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide 2, 2, 2-trifluoroacetate (543 mg, 1.05 mmol) in DCM (50 mL) was added TEA (424 mg, 4.19 mmol) at RT. The mixture was stirred at RT for 15 min and then Boc ₂O (362 mg, 1.68 mmol) was added. The resulting reaction mixture was stirred at RT for 3 hrs. The mixture was concentrated and the residue was purified by column on silica gel (PE/EA = 1.3/1) to give the title compound (520 mg, yield 96%) as a white solid. MS (ESI) : C ₂₅H ₂₈FN ₃O ₆S requires 517; found 462 [M-56+H] ⁺.

Descriptions 274-279

D274 to D279 were prepared using a similar procedure to that described for D273.

D274: (S) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D275: (R) -tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D276: (S) -tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D277 &D278: (R) -tert-butyl 4- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate and (S) -tert-butyl 4- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate

D279: tert-butyl 3- ( (1- ( (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) methyl) piperidine-1-carboxylate

Description 280

(R) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate (D280)

To a solution of (R) -tert-butyl 4- (2- (1- (6- (N, N-bis (2, 4-dimethoxybenzyl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-l-carboxylate (750 mg, 0.915 mmol) in DCM (7 mL) , TFA (1.5 mL, 19.47 mmol) was added dropwise. The mixture was stirred overnight. Solvent was removed under vacuum. The residue was for next step directly. To a solution of crude residue from previous step in DCM (10 mL) added sodium bicarbonate (1153 mg, 13.72 mmol) solution in water (12 mL) dropwise, followed by Boc ₂O (220 mg, 1.006 mmol) solution in DCM (2 mL) . The resulting reaction mixture was stirred overnight at RT and then filtered. The filtrate was diluted with DCM (10 mL) and water (5 mL) , and then seperated. The aqueous layer was extracted with DCM (10 mL) again. Combined organic layer was concentrated to dryness. The residue was purified with C18 reverse phase chromatography (ACN/H ₂O with 0.05%TFA, ACN%= 50%-80%) . Desired fractions were collected and neutralized with saturated NaHCO ₃ solution. Most ACN was removed by rotavap. The aqueous layer was extracted with EA (80 mL) . The organic layer was dried over Na ₂SO ₄. Filtered, the filtrate was concentrated to dryness and then freeze-dried to give the title compound (389.5 mg, 82 %) as a white solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.65 (dd, J= 1.8, 7.7 Hz, 1H) , 7.52 (dd, J= 6.4, 8.6 Hz, 1H) , 7.43-7.33 (m, 2H) , 7.29-7.26 (m, 1H) , 6.45 (d, J= 8.3 Hz, 1H) , 5.93 (q, J= 7.1 Hz, 1H) , 5.03 (s, 2H) , 4.35-3.99 (m, 2H) , 2.91-2.78 (m, 2H) , 2.76-2.61 (m, 1H) , 1.89 (d, J= 7.1 Hz, 3H) , 1.75-1.62 (m, 2H) , 1.51-1.37 (m, 10H) , 0.91-0.79 (m, 1H) . MS (ESI) : C ₂₅H ₃₀FN ₃O ₆S requires 519; found 542 [M+Na] ⁺.

Descriptions 281-282

D281 &D282 were prepared using a similar procedure to that described for D280.

D281: (R) -tert-butyl 4- (2- (1- (4-fluoro-2-oxo -6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

D282: (S) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

Description 283

tert-butyl 3-fluoro-3- (2- (1- (4-fluoro-6- (N- (4-methylthiazol-2-yl) sulfamoyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) azetidine-1-carboxylate (D283)

A solution of 4-methylthiazol-2-amine (32 mg, 0.28 mmol) , pyridine (66 mg, 0.85 mmol) and DMAP (17 mg, 0.14 mmol) in DCM (3 mL) was added tert-butyl 3- (2- (1- (6- (chlorosulfonyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -3-fluoroazetidine-1-carboxylate (150 mg, 0.28 mmol) . The mixture was stirred at RT for 2 hrs. The solvent was concentrated in vaccuo. The residue was purified by Prep-HPLC to give the title compound (35 mg, 21%) as a yellow solid. MS (ESI) : C ₂₇H ₂₈F ₂N ₄O ₆S ₂ requires 606; found 607 [M+H] ⁺.

Description 284

(R) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate (D284)

To a solid mixture of (R) -tert-butyl -4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate (241.7 mg, 0.465 mmol) , copper (I) iodide (167.7 mg, 0.881 mmol) and potassium carbonate (169 mg, 1.223 mmol) in 20 mL microwave vial, rac-(1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (130.6 mg, 0.918 mmol) solution in ACN (3 mL) (HPLC grade) was added, followed by 4-bromothiazole (220.6 mg, 1.345 mmol) solution in ACN (3 mL) (HPLC grade) . The mixture was bubbled with N ₂ flow for 1 min, then sealed. The reaction mixture was heated at 90℃ for 2 hrs and then cooled down to RT. To a solid mixture of (R) -tert-butyl -4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate (143 mg, 0.275 mmol) , copper (I) iodide (107.7 mg, 0.566 mmol) and potassium carbonate (97.8 mg, 0.708 mmol) in 5 mL microwave vial, rac- (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (81.6 mg, 0.574 mmol) solution in ACN (2 mL) (HPLC grade) was added, followed by 4-bromothiazole (113 mg, 0.688 mmol) solution in ACN (2 mL) (HPLC grade) . The mixture was bubbled with N ₂ flow for 1 min, then sealed. The reaction mixture was heated at 90℃ for 3.5 hrs and then cooled down to RT. The reaction mixture from two bottles was combined. Filtered, the filtrate was concentrated to dryness. The residue was purified with C18 reverse phase chromatography (ACN/water with 0.05%TFA, ACN%= 40%-90%) , to give the title compound (323 mg, 0.536 mmol, 72.4%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 11.42 (brs, 1H) , 8.76 (s, 1H) , 7.63 (d, J= 7.6 Hz, 1H) , 7.52 (dd, J= 6.5, 8.4 Hz, 1H) , 7.43-7.31 (m, 2H) , 7.26 (dd, J= 1.7, 7.6 Hz, 1H) , 6.88 (s, 1H) , 6.43 (d, J= 8.6 Hz, 1H) , 5.89 (q, J= 7.1 Hz, 1H) , 4.32-3.96 (m, 2H) , 2.91-2.74 (m, 2H) , 2.63 (t, J= 12.7 Hz, 1H) , 1.88 (d, J= 7.1 Hz, 3H) , 1.73-1.56 (m, 2H) , 1.50-1.35 (m, 10H) , 0.90-0.75 (m, 1H) . MS (ESI) : C ₂₈H ₃₁FN ₄O ₆S ₂ requires 602; found 625 [M+Na] ⁺.

Descriptions 285-287

D285-D287 were prepared using a similar procedure to that described for Description 284.

D285: (S) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

D286: (R) -tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

D287: (R) -tert-butyl 4- (2- (1- (6- (N- (1, 2, 4-thiadiazol-5-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-1-carboxylate

Description 288

(R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D288)

A mixture of (R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (110 mg, 0.224 mmol) , 2-bromothiazole (110 mg, 0.672 mmol) , N ¹, N ²-dimethylcyclohexane-1, 2-diamine (16 mg, 0.11 mmol) , CuI (21 mg, 0.11 mmol) and K ₂CO ₃ (62 mg, 0.45 mmol) in 1, 4-dioxane (3 mL) was stirred at 95℃ under N ₂ for 3 hrs. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE/EA = 1/1) to give the title compound (110 mg, 86%) as a yellow solid. MS (ESI) : C ₂₆H ₂₇FN ₄O ₆S ₂ requires 574; found 519 [M-56+H] ⁺.

Description 289

(R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D289)

A mixture of (R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (200 mg, 0.407 mmol) , 4-iodo-thiazole (270 mg, 1.22 mmol) , N ¹, N ²-dimethylcyclohexane-1, 2-diamine (29 mg, 0.20 mmol) , CuI (39 mg, 0.20 mmol) and Cs ₂CO ₃ (398 mg, 1.22 mmol) in ACN (5 mL) was stirred at 90℃ under N ₂ for 3 hrs. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on C18 (ACN/H ₂O = 5-95%) to give the title compound (135 mg, 58%) as a white solid. MS (ESI) : C ₂₆H ₂₇FN ₄O ₆S ₂ requires 574; found 519 [M-56+H] ⁺.

Description 290

(R) -tert-butyl 8- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (D290)

A mixture of (R) -tert-butyl 8- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (120 mg, 0.244 mmol) , 4-iodothiazole (155 mg, 0.733 mmol) , N ¹, N ²-dimethylcyclohexane-1, 2-diamine (17 mg, 0.12 mmol) , CuI (23 mg, 0.12 mmol) and Cs ₂CO ₃ (239 mg, 0.733 mmol) in ACN (3 mL) was stirred at 73℃ under N ₂ for 3 hrs. The mixture was cooled to RT and water (20 mL) was added. The mixture was extracted with CHCl ₃ (30 mL × 3) . The combined organic layers were dried over Na ₂SO ₄ and concentrated in vacuo to give a residue. The residue was purified by column chromatography on C 18 (ACN∶H ₂O = 40%-80%) to give the title compound (70 mg, 50%) as a yellow solid. MS (ESI) : C ₂₆H ₂₇FN ₄O ₆S ₂ requires 574; found 519 [M-56+H] ⁺.

Descriptions 291-304

D291-D304 were prepared using a similar procedure to that described for D290.

D291: (S) -tert-butyl 8- (1- (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate

D292: (R) -tert-butyl 4- (2- (1- (6- (N- (1, 2, 4-thiadiazol-5-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D293: (S) -tert-butyl 4- (2- (1- (6- (N- (1, 2, 4-thiadiazol-5-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D294 &D295: (R) -tert-butyl 4- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate and (S) -tert-butyl 4- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) isoindoline-2-carboxylate

D296: tert-butyl 3- ( (1- ( (7-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) methyl) cyclopropyl) methyl) piperidine-1-carboxylate

D297: (R) -tert-butyl 4- (2- (1- (6- (N- (1, 3, 4-thiadiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D298: (R) -tert-butyl 4- (2- (1- (7-fluoro-6- (N- (4-methylthiazol-2-yl) sulfamoyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D299: (R) -tert-butyl 4- (2- (1- (6- (N- (1, 3, 4-thiadiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D300: (R) -tert-butyl 4- (2- (1- (6- (N- (1, 2, 4-thiadiazol-5-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D301: (S) -tert-butyl 4- (2- (1- (6- (N- (1, 2, 4-thiadiazol-5-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D302: (R) -tert-butyl 4- (2- (1- (4-fluoro-6- (N- (4-methylthiazol-2-yl) sulfamoyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D303: tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

D304: tert-butyl 4- (2- (1- (6- (N- (4-cyanothiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Description 305

(R) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D305)

A mixture of (R) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6-sulfamoylbenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (40 mg, 0.077 mmol) , 4-bromothiazole (38 mg, 0.23 mmol) , N ¹, N ²-dimethylethane-1, 2-diamine (4 mg, 0.04 mmol) , CuI (7 mg, 0.04 mmol) and Cs ₂CO ₃ (50 mg, 0.15 mmol) in CH ₃CN (1.5 mL) was stirred at 100℃ under microwave for 2 hrs. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated and the residue was purified by prep-TLC (PE/EA = 1.5/1) to give the title compound (16 mg, yield 34%) as a white solid. MS (ESI) : C ₂₈H ₂₉FN ₄O ₆S ₂ requires 600; found 545 [M-56+H] ⁺.

Descriptions 306

D306 was prepared using a similar procedure to that described for D305.

D306: (S) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Description 307

4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D307)

A mixture of 4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (637 mg, 1.42 mmol) , 4-iodothiazole (597 mg, 2.83 mmol) , N ¹, N ²-dimethylcyclohexane-1, 2-diamine (402 mg, 2.83 mmol) , Cs2CO3 (1.38 g, 4.25 mmol) and CuI (134 mg, 0.707 mmol) in acetonitrile (25 mL) was degassed with N ₂ three times and stirred at 70℃ under N ₂ for 3 hrs. Then the mixture was cooled to RT and filtered. The filtrate was concentrated and the residue was purified by column chromatography C18 (5-50%ACN/H ₂O) to give the title compound (662 mg, 87%) as a yellow solid. ¹H NMR (300 MHz, CDCl ₃) : δ 8.25 (s, 1H) , 7.64-7.58 (m, 1H) , 7.47 (s, 1H) , 7.41-7.27 (m, 4H) , 6.02 (s, 1H) , 5.94-5.84 (m, 1H) , 4.86-4.66 (m, 1H) , 4.62-4.47 (m, 2H) , 3.82-3.71 (m, 1H) , 3.51-3.39 (m, 1H) , 1.89-1.87 (m, 3H) , 1.58-1.27 (m, 6H) .

Description 308

4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D308)

To a solution of 4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (660 mg, 1.23 mmol) in THF (20 mL) was added conc. HCl (10 mL) . Then the mixture was stirred at 40℃ for 4 hrs. The mixture was concentrated. The residue was purified by column chromatography C18 (5-60%ACN/H ₂O) to give the title compound (340 mg, 61%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d ₆) : δ 11.17 (s, 1H) , 8.89 (d, J= 1.8 Hz, 1H) , 7.64 (d, J= 1.2 Hz, 1H) , 7.55-7.52 (m, 2H) , 7.40-7.29 (m, 3H) , 7.10 (d, J = 2.1 Hz, 1H) , 5.88-5.82 (m, 1H) , 5.05-5.01 (m, 1H) , 4.55-4.49 (m, 1H) , 4.42-4.36 (m, 1H) , 1.83 (d, J= 6.6 Hz, 3H) .

Description 309

4-fluoro-3- (1- (2-formylphenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (D309)

To a solution of 4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (131 mg, 0.291 mmol) in DCM (8 mL) was added Dess-Martin periodinane (185 mg, 0.437 mmol) at RT. Then the mixture was stirred at RT for 1 hour. The mixture was concentrated under vacuum at RT. The residue was purified by pre-TLC (PE/EA= 3/2, twice) to give the title compound (84 mg, 65%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 10.11 (br s, 1H) , 10.06 (s, 1H) , 8.75 (d, J= 1.5 Hz, 1H) , 7.82 (dd, J= 7.2, 1.2 Hz, 1H) , 7.70 (d, J = 7.6 Hz, 1H) , 7.63 (t, J= 8.0 Hz, 1H) , 7.56 (t, J= 6.4 Hz, 1H) , 7.41-7.38 (m, 2H) , 7.10 (d, J= 2.0 Hz, 1H) , 6.65-6.59 (m, 1H) , 1.95 (d, J= 7.2 Hz, 3H) .

Description 310

tert-butyl (2- ( (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) benzyl) amino) ethyl) carbamate (D310)

To a solution of 4-fluoro-3- (1- (2-formylphenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (84 mg, 1.89 mmol) and tert-butyl (2-aminoethyl) carbamate (90 mg, 0.56 mmol) in DCE (8 mL) was added acetic acid (1 drop) and NaBH (OAc) 3 (120 mg, 0.56 mmol) . The resulting mixture was stirred at RT overnight. Water (10 mL) was added and CH ₂Cl ₂ (20 mL × 2) was added to extract the title compound. The combined organic layer was washed with brine (30 mL) , dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (124 mg with 65%purity, 73%) as a yellow solid which was used for next step directly. MS (ESI) : C ₂₆H ₃₀FN ₅O ₆S ₂ requires 591; found 592 [M+H] ⁺.

Descriptions 311-312

(R) -tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate & (S) -tert-butyl 4- (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (D311 &D312)

tert-Butyl 4- (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (150 mg, 0.25 mmol) was purified by Chiral-HPLC (Chiralpak IC, 5um, 2.1 ×25 cm, Phase: Hex∶EtOH∶DEA = 40∶60∶0.2) to give the title compounds isomer 1 (52 mg, 35%) and isomer 2 (55 mg, 37%) as yellow solid. Isomer 1: Chiral-HPLC: rt = 6.506 min; ＞99%ee; MS (ESI) : C ₂₈H ₂₉FN ₄O ₆S ₂ requires 600; found 601 [M+H] ⁺; Isomer 2: Chiral-HPLC: rt = 10.884 min; ＞99%ee; MS (ESI) : C ₂₈H ₂₉FN ₄O ₆S ₂ requires 600; found 601 [M+H] ⁺.

Example 1

7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E1)

A solution of tert-butyl 8- (1- (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (60 mg, 0.08 mmol) in DCM/TFA (2 mL/2 mL) was stirred at RT for 30 min. The reaction solution was concentrated. The residue was purified by Prep-HPLC to give the title compound (24 mg, 54.7%) as a white solid in HCl salt. ¹H NMR (400 MHz, CD ₃OD) : δ 7.77 (d, J= 7.6 Hz, 1H) , 7.63-7.59 (m, 1H) , 7.47 (t, J= 8.0 Hz, 1H) , 7.31 (d, J= 7.6 Hz, 1H) , 7.12 (d, J= 4.8 Hz, 1H) , 6.81 (d, J= 8.4 Hz, 1H) , 6.74 (d, J= 4.4 Hz, 1H) , 5.71 (q, J= 6.8 Hz, 1H) , 4.47 (d, J= 16.0 Hz, 1H) , 4.13 (d, J= 16.0 Hz, 1H) , 3.51-3.45 (m, 1H) , 3.37-3.29 (m, 1H) , 3.16-3.04 (m, 2H) , 1.91 (d, J= 7.2 Hz, 3H) . MS (ESI) : C ₂₁H ₁₉FN ₄O ₄S ₂ requires 474; found 475 [M+H] ⁺.

Examples 2-56

Examples 2 to 56 were prepared using a similar procedure to that described for E1, with the specified reaction reagents, temperature or solvent as listed in the table.

E2: 3- (1- (2- (aminomethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E3: 3- (1- (2- (aminomethyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E4: 7-fluoro-2-oxo-3- (1- (2- (pyrrolidin-3-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E5: 3- (1- (2- (2-amino-1, 1-difluoroethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E6: 3- (1- (2- (2-amino-1, 1-difluoroethyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E7: 3- ( (1- (3-aminopropyl) cyclopropyl) methyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E8: 4-fluoro-2-oxo-3- (1- (1- (piperidin-4-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E9: 7-fluoro-2-oxo-3- (1- (1- (piperidin-4-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamide hydrochloride,

E10: 4-fluoro-2-oxo-3- (1- (1- (piperidin-3-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E11: 7-fluoro-2-oxo-3- (1- (1- (piperidin-3-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamide hydrochloride,

E12: 7-fluoro-2-oxo-3- ( (1- (piperidin-2-yl) cyclopropyl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E13: 7-fluoro-2-oxo-3- (1- (1- (piperidin-2-yl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E14: 3- (1- (1- (3-aminopropyl) cyclopropyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E15: 3- (1- (2- (2-aminoethyl) -3-fluorophenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E16: 4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (5-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E17: 7-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (6-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E18: 4-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E19: 7-fluoro-2-oxo-3- (1- (1- (piperidin-3-ylmethyl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E20: 3- (2- (aminomethyl) -3-methylbenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E21: 2- ( (2- ( (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) methyl) -6-methylbenzyl) amino) acetamide hydrochloride,

E22: 7-fluoro-2-oxo-3- ( (1- (piperidin-4-ylmethyl) cyclopropyl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E23: 3- ( (1- (2-aminoethyl) cyclopropyl) methyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E24: 3- (1- (1- (2-aminoethyl) cyclopropyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E25: 3- (1- (2- (2-aminoethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E26: 3- ( (7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) methyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E27: 3- (1- (2- ( (dimethylamino) methyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E28: 3- (1- (2- ( (dimethylamino) methyl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E29: 3- (1- (2- (aminomethyl) -3-methylphenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E30: 3- (1- (2- (aminomethyl) -3-methylphenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E31: 7-fluoro-2-oxo-3- (1- (1- (piperidin-4-ylmethyl) cyclopropyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E32 &E33: (R) -7-fluoro-N- (6-fluoropyridin-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and (S) -7-fluoro-N- (6-fluoropyridin-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E34 &E35: 3- ( (R) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide and 3- ( (S) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

E36: 3- (1- ( (S/R) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E37 &E38: 3- ( (R) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and 3- ( (S) -1- ( (R/S) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E39: 3- (1- ( (S/R) -7-amino-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E40 &E41: (R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and (S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E42 &E43: (R) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and (S) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E44 &E45: (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and (S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E46: 4-fluoro-3- (1- (2- (3-methoxyazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E47: 7-fluoro-3- (1- (2- (3-methoxyazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E48: 3- (1- (2- (azetidin-3-yl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E49: 3- (1- (2- (azetidin-3-yl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E50: 3- (1- (2- (azetidin-1-yl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

E51: 3- (1- (2- (azetidin-1-yl) phenyl) ethyl) -7-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-

dihydrobenzo [d] oxazole-6-sul fonamide,

E52: 4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (6-fluoropyridin-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

E53: 7-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (isoxazol-3-yl) -2-oxo-2, 3-

dihydrobenzo [d] oxazole-6-sulfonamide,

E54: (R) -4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

E55: (S) -4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

E56: (R) -7-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide,

Example 57

4-fluoro-2-oxo-3- ( (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E57)

To a solution of tert-butyl 8- ( (6- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -4-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) methyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (100 mg, 0.140 mmol) in DCM (5 mL) was added TFA (0.5 mL) . The resulting solution was stirred at RT for 1 hour. The solution was concentrated under vacuum and the residue was diluted with NaHCO ₃ (sat., 5 mL) . The mixture was stirred at RT for 20 min. The mixture was filtered and the precipitate was dried in vacuo. The solid was dissolved in HCl/MeOH (4 M, 8 mL) . The mixture was stirred at RT overnight. The mixture was filtered and the precipitate was dried under vacuum. MeOH (5 mL) was added and the mixture was stirred in reflux for 30 min. The mixture was cooled to RT and filtered. The solid was collected and dried to give the title compound (55 mg, 79%) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.92 (s, 1H) , 9.46 (s, 2H) , 7.67 (s, 1H) , 7.51 (d, J= 10.4 Hz, 1H) , 7.29 (d, J= 4.4 Hz, 1H) , 7.24-7.18 (m, 2H) , 7.07 (d, J= 6.8 Hz, 1H) , 6.88 (d, J= 4.4 Hz, 1H) , 5.06 (s, 2H) , 4.35 (s, 2H) , 3.35-3.32 (m, 2H) , 3.06-3.03 (m, 2H) . MS (ESI) : C ₂₀H ₁₇FN ₄O ₄S ₂ requires 460; found 461 [M+H] ⁺.

Example 58

7-fluoro-2-oxo-3- ( (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E58)

Examples 58 was prepared using a similar procedure to that described for Example 57, with the specified reaction reagents, temperature or solvent as listed in the table.

Example 59

3- (2- ( (dimethylamino) methyl) -3-methylbenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E59)

To a round bottom flask was added 3- (2- (aminomethyl) -3-methylbenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide, hydrochloride (45 mg, 0.093 mmol) in DCM (10 mL) . To the reaction mixture was added sodium triacetoxyborohydride (983 mg, 4.64 mmol) and formaldehyde (1.382 mL, 18.56 mmol) at RT over 10 days. The crude product was added to a C 18 reverse phase column, eluting with MeCN/TFA0.5% (0%to 100%) , to give the title compound (10 mg, 0.018 mmol, 18.9%) . ¹H NMR (600MHz, DMSO-d ₆) δ 12.94 (br. S., 1H) , 10.08 (br. S., 1H) , 7.69-7.64 (m, 1H) , 7.50 (d, J= 9.9 Hz, 1H) , 7.32-7.25 (m, 3H) , 7.08 (d, J= 7.3 Hz, 1H) , 6.88 (d, J = 4.6 Hz, 1H) , 5.41 (s, 2H) , 4.54 (d, J= 5.1 Hz, 2H) , 2.82 (d, J= 3.9 Hz, 6H) , 2.52 (s, 3H) . MS (ESI) : C ₂₁H ₂₁FN ₄O ₄S ₂ requires 476; found 477 [M+H] ⁺.

Example 60

2- ( (2- (1- (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) benzyl) amino) acetic acid hydrochloride (E60)

The mixture of 3- (1- (2- (aminomethyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (40 mg, 0.083 mmol) , 2-oxoacetic acid hydrate (6.1 mg, 0.083 mmol) and TEA (16.7 mg, 0.165 mmol) in THF (2.0 mL) was stirred at RT for 30 min. Then Na (CN) BH ₃ (15.6 mg, 0.248 mmol) was added in portions at 0℃. The reaction was stirred at RT for 3 hrs. To the mixture was added 2 drops of HCl (1M) . THF in the solution was removed under reduced pressure and the resulting mixture was purified by Prep-HPLC to afford the title compound (17 mg, 37.97%) as a white solid in HCl salt. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.89 (brs, 1H) , 9.55 (brs, 2H) , 7.67 (d, J = 7.6 Hz, 1H) , 7.61-7.56 (m, 2H) , 7.52-7.43 (m, 3H) , 7.28 (d, J= 4.4 Hz, 1H) , 6.87 (d, J= 4.0 Hz, 1H) , 5.96 (q, J= 6.8 Hz, 1H) , 4.28-4.17 (m, 2H) , 3.93 (s, 2H) , 1.82 (d, J= 6.8 Hz, 3H) . MS (ESI) : C ₂₁H ₁₉FN ₄O ₆S ₂ requires 506; found 507 [M+H] ⁺.

Example 61

2- ( (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) benzyl) amino) acetic acid hydrochloride (E61)

Example 61 was prepared using a similar procedure to that described for E60.

Example 62

4-fluoro-3- (1- (2- (hydroxymethyl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (E62)

To a solution of N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-3- (1- (2- ( ( (tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (50 mg, 0.073 mmol) in DCM (10 mL) was added TFA (0.5 mL) . Then the mixture was stirred at RT for 2 hrs. The mixture was concentrated and the residue was washed with MeOH (3 mL) and filtered. The filtrate was concentrated in vacuo. The crude was purified by prep-HPLC to give the title compound (10.6 mg, 32%) as a grey solid. ¹H NMR (400 MHz, CDCl ₃+CD ₃OD) : δ 7.61-7.57 (m, 1H) , 7.55-7.48 (m, 1H) , , 7.42-7.40 (m, 1H) , 7.36-7.26 (m, 3H) , 6.93-6.88 (m, 1H) , 6.55-6.51 (m, 1H) , 5.98-5.85 (m, 1H) , 4.69-4.61 (m, 1H) , 4.55-4.44 (m, 1H) , 1.93-1.87 (m, 3H) . MS (ESI) : C ₁₉H ₁₆FN ₃O ₅S ₂ requires 449; found 450 [M+H] ⁺.

Example 63

(R) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E63)

To a solution of (R) -tert-butyl -4- (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) piperidine-l-carboxylate (320 mg, 0.531 mmol) in DCM (6 mL) , TFA (1 mL, 12.98 mmol) was added dropwise. The reaction mixture was stirred for 1 hour. Solvent was removed under vacuum. The residue was purified with C 18 reverse phase chromatography (ACN/0.05%HCl in H ₂O, ACN%= 0%-70%) , to give (252 mg, 0.444 mmol, 84%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) 11.44 (s, 1H) , 8.89 (d, J= 2.2 Hz, 1H) , 8.86-8.74 (m, 2H) , 7.67 (dd, J= 1.1, 7.8 Hz, 1H) , 7.61 (dd, J= 6.4, 8.6 Hz, 1H) , 7.42-7.36 (m, 1H) , 7.35-7.29 (m, 1H) , 7.25 (dd, J= 1.6, 7.7 Hz, 1H) , 7.13 (d, J= 8.6 Hz, 1H) , 7.04 (d, J= 2.2 Hz, 1H) , 5.89 (q, J= 7.1 Hz, 1H) , 3.39 (d, J= 12.2 Hz, 1H) , 3.28 (d, J= 12.0 Hz, 1H) , 3.14-3.04 (m, 1H) , 2.98-2.85 (m, 1H) , 2.74-2.61 (m, 1H) , 2.00-1.72 (m, 6H) , 1.28 (d, J= 13.7 Hz, 1H) . MS (ESI) : C ₂₃H ₂₃FN ₄O ₄S ₂ requires 502; found 503 [M+H] ⁺.

Example 64

(R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E64)

To a solution of (R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (195 mg, 0.339 mmol) in MeOH (5 mL) was added HCl · (12 M, 0.5 mL) at RT. The mixture was stirred at RT for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on C18 (ACN/0.1%HCl in H ₂O= 5-95%) to give the title compound (150 mg, 87%) as a yellow solid. ¹H NMR (400 MHz, CD ₃OD) : δ 8.74 (d, J= 2.4 Hz, 1H) , 7.61-7.57 (m, 2H) , 7.51 (dd, J= 10.4, 1.6 Hz, 1H) , 7.37 (t, J= 7.6 Hz, 1H) , 7.26 (d, J= 7.6 Hz, 1H) , 7.11 (d, J= 2.4 Hz, 1H) , 5.78 (q, J= 7.2 Hz, 1H) , 4.48 (d, J= 15.6 Hz, 1H) , 4.20 (d, J= 15.6 Hz, 1H) , 3.52-3.46 (m, 1H) , 3.40-3.34 (m, 1H) , 3.21-3.05 (m, 2H) , 1.90 (d, J= 7.2 Hz, 3H) . MS (ESI) : C ₂₁H ₁₉FN ₄O ₄S ₂ requires 474; found 475 [M+H] ⁺.

Example 65

(R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E65)

To a solution of (R) -tert-butyl 8- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (63 mg, 0.11 mmol) in MeOH (3 mL) was added HCl· (12 M, 0.1 mL) at RT. The mixture was stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on C18 (ACN/0.1%HCl in H ₂O= 5-40%) to give the title compound (52.6 mg, 94%) as a white solid. ¹H NMR (400 MHz, CD ₃OD) : δ 8.72 (s, 1H) , 7.76-7.75 (m, 1H) , 7.59-7.56 (m, 1H) , 7.48-7.45 (m, 1H) , 7.31 (d, J= 7.2 Hz, 1H) , 7.03 (s, 1H) , 6.85 (d, J= 7.6 Hz, 1H) , 5.74-5.67 (m, 1H) , 4.49 (d, J= 15.6 Hz, 1H) , 4.17 (d, J= 15.2 Hz, 1H) , 3.52-3.46 (m, 1H) , 3.38-3.34 (m, 1H) , 3.20-3.05 (m, 2H) , 1.90 (d, J= 6.4 Hz, 3H) . MS (ESI) : C ₂₁H ₁₉FN ₄O ₄S ₂ requires 474; found 475 [M+H] ⁺.

Example 66

(R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl)ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E66)

To a solution of (R) -tert-butyl 8- (1- (4-fluoro-2-oxo-6- (N- (thiazol-2-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (100 mg, 0.174 mmol) in MeOH (3 mL) was added HCl (12 M, 0.5 mL) at RT. The mixture was stirred at RT for 10 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on C18 (ACN/0.1%HCl in H ₂O, ACN%= 5-95%) to give the title compound (30 mg, 34%) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.85 (br s, 1H) , 9.15-8.98 (m, 2H) , 7.62 (d, J= 1.6 Hz, 1H) , 7.50-7.47 (m, 2H) , 7.37-7.33 (m, 1H) , 7.28-7.27 (m, 1H) , 7.24-7.22 (m, 1H) , 6.88-6.87 (m, 1H) , 5.77 (q, J= 6.8 Hz, 1H) , 4.33-4.29 (m, 1H) , 4.12-4.07 (m, 1H) , 3.26-3.19 (m, 1H) , 3.09-2.93 (m, 3H) , 1.81 (d, J= 6.4 Hz, 3H) . MS (ESI) : C ₂₁H ₁₉FN ₄O ₄S ₂ requires 474; found 475 [M+H] ⁺.

Examples 67-88

Examples 67 to 88 were prepared using a similar procedure to that described for E66, with the specified reaction reagents, temperature or solvent as listed in the table.

E67: (S) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E68: 4-fluoro-3- (1- (2- (3-fluoroazetidin-3-yl) phenyl) ethyl) -N- (4-methylthiazol-2-yl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sul fonamide hydrochloride,

E69: N- (4-cyanothiazol-2-yl) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E70: 7-fluoro-2-oxo-3- ( (1- (piperidin-3-ylmethyl) cyclopropyl) methyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E71 &E72: (R) -7-fluoro-3- (1- (isoindolin-4-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and (S) -7-fluoro-3- (1- (isoindolin-4-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E73: 3- (1- (2- ( ( (2-aminoethyl) amino) methyl) phenyl) ethyl) -4-fluoro-2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide dihydrochloride,

E74: (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E75: (S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E76: (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamide hydrochloride,

E77: (S) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E78: (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 3, 4-thiadiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E79: (R) -7-fluoro-N- (4-methylthiazol-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E80: (R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 3, 4-thiadiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E81: (R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E82: (S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E83: (R) -4-fluoro-N- (4-methylthiazol-2-yl) -2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E84 &E85: (R) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride and (S) -4-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E86: (R) -4-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E87: (S) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E88: (R) -4-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

Examples 89-90

rac-4-fluoro-3- ( (R) -1- ( (R) -7-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide &rac-4-fluoro-3- ( (R) -1- ( (S) -7-hydroxy-5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (E89 &E90)

To a round bottom flask was added 3- (1- (7- ( (tert-butyldimethylsilyl) oxy) -5, 6, 7, 8-tetrahydronaphthalen-1-yl) ethyl) -N- (2, 4-dimethoxybenzyl) -4-fluoro-2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (330 mg, 0.438 mmol) and TFA (0.2 mL) in DCM (4 mL) . The solution was stirred at RT for 1 hour. To the reaction mixture was then added TFA (0.2 mL) and the reaction mixture was stirred for another 2.5 hrs. The reaction mixture was concentrated under reduced pressure. The crude product was added to a C18 reverse phase column and was eluted with ACN/TFA 0.1%in H ₂O (5%to 95%) . The purified products were dissolved in DMF (5 mL) and purified by MADP by ACN/TFA. The solvent was freeze dried to give the title compounds (35 mg, 0.069 mmol, 17%and 32 mg, 0.062 mmol, 14%) . Compound 1: ¹H NMR (400MHz, DMSO-d ₆) δ 12.86 (br. s., 1H) , 7.59 (d, J= 1.2 Hz, 1H) , 7.48 (dd, J= 1.1, 10.4 Hz, 1H) , 7.33 -7.20 (m, 2H) , 7.11 (t, J= 7.6 Hz, 1H) , 7.07 -6.99 (m, 1H) , 6.87 (d, J= 4.5 Hz, 1H) , 5.68 (q, J= 6.8 Hz, 1H) , 3.94 (d, J= 6.1 Hz, 1H) , 2.87 (td, J= 6.1, 16.7 Hz, 1H) , 2.77 -2.54 (m, 3H) , 1.85 -1.71 (m, 4H) , 1.69 -1.54 (m, 1H) . MS (ESI) : C ₂₂H ₂₀FN ₃O ₅S ₂ requires 489; found 490 [M+H] ⁺; Compound 2: ¹H NMR (400MHz, DMSO-d ₆) δ 12.87 (br. s., 1H) , 7.60 (d, J= 1.3 Hz, 1H) , 7.47 (dd, J= 1.3, 10.5 Hz, 1H) , 7.34-7.25 (m, 2H) , 7.19 -7.10 (m, 1H) , 7.04 (d, J = 7.6 Hz, 1H) , 6.87 (d, J= 4.6 Hz, 1H) , 5.69 (q, J= 7.1 Hz, 1H) , 3.88 -3.77 (m, 1H) , 2.96 (dd, J= 4.7, 16.3 Hz, 1H) , 2.88 -2.65 (m, 2H) , 2.16 (dd, J= 8.5, 16.3 Hz, 1H) , 1.94 -1.72 (m, 4H) , 1.57 -1.38 (m, 1H) . MS (ESI) : C ₂₂H ₂₀FN ₃O ₅S ₂ requires 489; found 490 [M+H] ⁺.

Example 91

4-fluoro-3- (1- (2- (morpholinomethyl) phenyl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E91)

To a mixture of 4-fluoro-3- (1- (2- (morpholinomethyl) phenyl) ethyl) -2-oxo-2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (63 mg, 0.15 mmol) , 2-bromothiazole (95 mg, 0.56 mmol) , N ¹, N ²-dimethylcyclohexane-1, 2-diamine (41 mg, 0.29 mmol) in DMF (35 mL) was added K ₂CO ₃ (80 mg, 0.58 mmol) and CuI (55 mg, 0.29 mmol) . The mixture was degassed with N ₂ three times and stirred at 80℃ under N ₂ for 2 hrs. Then the mixture was cooled to RT and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (5-80%EA in PE) and further purified by column chromatography C18 (ACN in water, from 5%to 45%) to give the crude product (27 mg) as a white solid. The crude product was dissolved in water (2 mL) and 3 drops of conc. HCl. The mixture was purified by prep-HPLC (ACN in 0.1%HCl, from 2%to 45%) to give the title compound (22 mg, 27%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.93 (br s, 1H) , 11.29 (br s, 1H) , 7.82-7.75 (m, 1H) , 7.71-7.64 (m, 2H) , 7.61-7.43 (m, 3H) , 7.28 (s, 1H) , 6.88 (s, 1H) , 6.24-6.12 (m, 1H) , 4.55-4.34 (m, 2H) , 4.04-3.83 (m, 4H) , 3.30-3.08 (m, 4H) , 1.85 (s, 3H) . MS (ESI) : C ₂₃H ₂₃FN ₄O ₅S ₂ requires 518; found 519 [M+H] ⁺.

Example 92

4-fluoro-3- (1- (2- ( ( (2-hydroxyethyl) amino) methyl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E92)

To a solution of 4-fluoro-3- (1- (2-formylphenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (45 mg, 0.10 mmol) and 2-aminoethanol (18 mg, 0.30 mmol) in DCE (5 mL) was added acetic acid (1 drop) and NaBH (OAc) ₃ (63 mg, 0.30 mmol) . The resulting mixture was stirred at RT overnight. Then the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column C18 (ACN in 0.1%HCl, from 5%to 60%) to give the title compound (6.2 mg, 11%) as a grey solid. ¹H NMR (400 MHz, CD ₃OD) : δ 8.74 (br s, 1H) , 7.80-7.78 (m, 1H) , 7.61 (s, 1H) , 7.57-7.45 (m, 4H) , 7.12 (s, 1H) , 6.03 (q, J= 7.2 Hz, 1H) , 4.43-4.33 (m, 2H) , 3.90-3.84 (m, 2H) , 3.27-3.24 (m, 2H) , 1.94 (d, J= 6.8 Hz, 3H) . MS (ESI) : C ₂₁H ₂₁FN ₄O ₅S ₂ requires 492; found 493 [M+H] ⁺.

Example 93

(R) -7-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E93)

To a solution of (R) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (26.3 mg, 0.049 mmol) and formaldehyde (37%in water, 0.08 mL, 1.075 mmol) in MeOH (5 mL) , sodium triacetoxyhydroborate (38.8 mg, 0.146 mmol) was added in small portions. The reaction mixture was stirred for 10 min at RT and then quenched with saturated NH ₄Cl solution. To a solution of (R) -7-fluoro-2-oxo-3- (1- (2- (piperidin-4-yl) phenyl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (92.2 mg, 0.171 mmol) and formaldehyde (37%in water, 0.26 mL, 3.49 mmol) in MeOH (15 mL) , sodium triacetoxyhydroborate (138.9 mg, 0.524 mmol) was added in small portions. The reaction mixture was stirred for 25 min at RT. Quenched with saturated NH ₄Cl solution. The reaction mixture from two bottles were combined and concentrated. The residue was purified with C18 reverse phase chromatography, eluting with ACN/0.05%HCl in H ₂O (ACN%= 0%-60%) , to give the title compound (110.5 mg, 91.2%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d ₆) 11.43 (s, 1H) , 10.52 (brs, 1H) , 8.88 (d, J= 2.2 Hz, 1H) , 7.67 (dd, J = 1.0, 7.6 Hz, 1H) , 7.60 (dd, J= 6.7, 8.4 Hz, 1H) , 7.43-7.37 (m, 1H) , 7.35-7.30 (m, 1H) , 7.29-7.25 (m, 1H) , 7.08 (d, J = 8.6 Hz, 1H) , 7.05 (d, J= 2.0 Hz, 1H) , 5.88 (q, J= 7.1 Hz, 1H) , 3.50 (d, J= 12.0 Hz, 1H) , 3.39 (d, J= 12.7 Hz, 1H) , 3.12-2.91 (m, 2H) , 2.84-2.68 (m, 4H) , 2.15-1.88 (m, 3H) , 1.83 (d, J= 7.1 Hz, 3H) , 1.35 (d, J= 13.9 Hz, 1H) . MS (ESI) : C ₂₄H ₂₅FN ₄O ₄S ₂ requires 516; found 517 [M+H] ⁺.

Example 94

(R) -4-fluoro-3- (1- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2-oxo-N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide (E94)

To a solution of (R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-2-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (98 mg, 0.19 mmol) in MeOH (10 mL) was added formaldehyde (37%, aq., 0.5 mL) and NaBH (OAc) ₃ (407 mg, 1.92 mmol) . The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on C18 (ACN/0.1% NH ₄HCO ₃ in H ₂O = 5-95%) to give the title compound (20 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD ₃OD) : δ 7.58 (d, J= 1.2 Hz, 1H) , 7.45-7.38 (m, 2H) , 7.26-7.22 (m, 1H) , 7.14 (d, J= 7.2 Hz, 1H) , 7.07 (d, J= 4.4 Hz, 1H) , 6.68 (d, J= 4.4 Hz, 1H) , 5.76 (q, J= 6.8 Hz, 1H) , 3.91-3.87 (m, 1H) , 3.44-3.40 (m, 1H) , 3.08-2.88 (m, 3H) , 2.73-2.67 (m, 1H) , 2.51 (s, 3H) , 1.89 (d, J= 6.8 Hz, 3H) . MS (ESI) : C ₂₂H ₂₁FN ₄O ₄S ₂ requires 488; found 489 [M+H] ⁺.

Example 95

(R) -4-fluoro-3- (1- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E95)

To a solution of (R) -4-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (70 mg, 0.14 mmol) in MeOH (6 mL) was added formaldehyde (37%, aq., 1 mL) and NaBH (OAc) ₃ (290 mg, 0.137 mmol) at RT. The reaction mixture was stirred at RT for 2 hrs. Water (20 mL) was added to the mixture at 0℃. Then the mixture was extracted with CHCl ₃ (30 mL×3) . The combined organic layer was dried over Na ₂SO ₄, filtered and concentrated in vacuo to give the residue. The residue was purified by column on C18 using ACN/0.1%HCl in H ₂O = 5-95%to give the title compound (20 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD ₃OD) : δ 8.69 (d, J = 2.0 Hz, 1H) , 7.61-7.57 (m, 2H) , 7.51-7.48 (m, 1H) , 7.39 (t, J= 8.0 Hz, 1H) , 7.29-7.27 (m, 1H) , 7.09 (d, J= 2.0 Hz, 1H) , 5.79 (q, J= 6.8 Hz, 1H) , 4.64-4.14 (m, 2H) , 3.66-3.36 (m, 2H) , 3.26-3.14 (m, 2H) , 3.03 (s, 3H) , 1.90 (d, J = 6.8 Hz, 3H) . MS (ESI) : C ₂₂H ₂₁FN ₄O ₄S ₂ requires 488; found 489 [M+H] ⁺.

Examples 96-98

Examples 96 to 98 were prepared using a similar procedure to that described for E95, with the specified reaction reagents, temperature or solvent as listed in the table.

E96: (R) -4-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

E97: (S) -7-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sul fonamide hydrochloride,

E98: (R) -4-fluoro-3- (1- (2- (1-methylpiperidin-4-yl) phenyl) ethyl) -2-oxo-N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride,

Example 99

(R) -7-fluoro-3- (1- (2- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E99)

A solution of (R) -tert-butyl 4- (2- (1- (7-fluoro-2-oxo-6- (N- (thiazol-4-yl) sulfamoyl) benzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (820 mg, 1.365 mmol) was dissolved in DCM (13.0 mL) at 0 ℃. TFA (2.60 mL, 33.7 mmol) was then added. The solution was stirred at 0℃ for 1 h. The reaction solution was concentrated under vacuum. The residue was dissolved in methanol (13.0 mL) and stirred with formaldehyde (5.0 mL, 67.2 mmol) at RT for 20 min. After adding sodium triacetoxyborohydride (1491 mg, 6.83 mmol) , the reaction was stirred for another 1 h. The reaction solution was concentrated under vacuum and purified by chromatography (ACN: H ₂O/0.05%HCl = 0～30%) to give the title compound (609 mg, 1.050 mmol, 77 %yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.40 (s, 1 H) 11.07 (br. s., 0.5 H) 10.92 (br. s., 0.5 H) 8.89 (d, J = 2.20 Hz, 1 H) 7.77-7.72 (m, 1 H) 7.67-7.59 (m, 1 H) 7.43-7.35 (m, 2 H) 7.18-6.98 (m, 3 H) 5.75 (q, J= 7.05 Hz, 0.5 H) 5.66-5.60 (m, 1 H) 5.29 (br. s., 0.5 H) 3.81 (t, J=14.00 Hz, 1 H) 3.63-3.39 (m, 2 H) 3.29-3.00 (m, 1 H) 2.86 (d, J=3.30 Hz, 3.5 H) 2.62 (br. s., 1 H) 2.07 (d, J= 17.24 Hz, 0.5 H) 1.83 (d, J= 7.09 Hz, 3 H) . MS (ESI) : C ₂₄H ₂₃FN ₄O ₄S ₂ requires 514; found 515 [M+H] ⁺.

Example 100

(R) -7-fluoro-3- (1- (2- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2-oxo-N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E100)

To a solution containing (R) -tert-butyl 4- (2- (1- (6- (N- (1, 2, 4-thiadiazol-5-yl) sulfamoyl) -7-fluoro-2-oxobenzo [d] oxazol-3 (2H) -yl) ethyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (390 mg, 0.648 mmol) in DCM (5 mL) was added TFA (1.998 mL, 25.9 mmol) at RT. The reaction mixture was stirred at the same temperature for 4 hrs. The the reaction mixture was concentrated. The residue was purified with C18 reverse phase chromotagraphy with ACN/HCl (5%in H ₂O) = 0%to 100%to give (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (284 mg, 0.523 mmol, 81%yield) as a white solid. To a round bottom flask containing (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (146 mg, 0.271 mmol) ) , formaldehyde (0.808 mL, 10.85 mmol) in DMSO (2 mL) was added sodium triacetoxyborohydride (288 mg, 1.357 mmol) . The reaction mixture was stirred. To a round bottom flask containing (R) -7-fluoro-2-oxo-3- (1- (2- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -N- (1, 2, 4-thiadiazol-5-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (5 mg, 9.29 μmol) , formaldehyde (0.028 mL, 0.372 mmol) in DMSOl (0.5 mL) was added sodium triacetoxyborohydride (7.88 mg, 0.037 mmol) . The reaction mixture was stirred for 3 hrs. The reaction mixture from two batches was combined and purfied with C18 reverse phase chromotagraphy with (H ₂O (0.05%HCl) /ACN=100%-0%, to give the title compound (140 mg, 0.251 mmol, 93 %yield) as a white solid. ¹H NMR (600MHz, MeOD-d ₄) 8.22 (s, 1H) , 7.92-7.77 (m, 1H) , 7.67 -7.56 (m, 1H) , 7.48 (td, J= 7.4, 15.3 Hz, 1H) , 7.40 (t, J= 7.4 Hz, 1H) , 7.25 -7.10 (m, 1H) , 6.88 (d, J= 8.4 Hz, 0.5H) , 6.77 (d, J= 8.3 Hz, 0.5H) , 5.93 -5.86 (m, 0.5H) , 5.79-5.73 (m, 0.5H) , 5.60 (br. s., 0.5H) , 5.19 (br. s., 0.5H) , 4.04 -3.87 (m, 1H) , 3.74 (d, J= 16.1 Hz, 0.5H) , 3.68 -3.53 (m, 1.5H) , 3.50 -3.41 (m, 0.5H) , 3.25 -3.17 (m, 0.5H) , 3.02 (s, 3H) , 2.92-2.81 (m, 0.5H) , 2.80 -2.71 (m, 0.5H) , 2.65 -2.56 (m, 0.5H) , 2.08 (br. s., 0.5H) , 1.92 (d, J= 7.0 Hz, 3H) . MS (ESI) : C ₂₃H ₂₂FN ₅O ₄S ₂ requires 515; found 516 [M+H] ⁺.

Example 101

(R) -7-fluoro-3- (1- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (E101)

To a solution of (R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride (186 mg, 0.364 mmol) in MeOH (10 mL) was added formaldehyde (37%, 1.20 mL) at RT. The reaction mixture was stirred for 20 min, and followed by addition of NaBH (OAc) ₃ (398 mg, 1.82 mmol) at RT. The reaction mixture was stirred at RT for another 1 h and then concentrated under reduced pressure. The residue was purified by reverse column (C18) using ACN/0.05%HCl in H ₂O= 0-50%to give the title compound (190 mg, 99%) as an off-white solid. ¹H NMR (400 MHz, Methanol-d ₄) δ 8.70 -8.79 (m, 1 H) , 7.67 -7.80 (m, 1 H) , 7.41 -7.64 (m, 2 H) , 7.28 -7.37 (m, 1 H) , 7.01 -7.07 (m, 1 H) , 6.78 (d, J= 8.44 Hz, 1 H) , 5.59 -5.82 (m, 1 H) , 4.51 -4.71 (m, 1 H) , 4.10 (m, 1 H) , 3.68 (m, 1 H) , 3.32 -3.43 (m, 1 H) , 3.06 -3.26 (m, 2 H) , 2.95 -3.05 (m, 3 H) , 1.90 (d, J= 9.17 Hz, 3 H) . MS (ESI) : C ₂₂H ₂₁FN ₄O ₄S ₂ requires 488; found 489 [M+H] ⁺. The title compound was further treated with reverse column (C18) using ACN/0.05%NH ₄OH in H ₂O= 0-50%to give the free base form of the title compound as a white solid. ¹H NMR (400 MHz, Methanol-d ₄) δ 8.65 (s, 1 H) , 7.59 (d, =7.70 Hz, 1 H) , 7.47 (dd, J = 8.44, 6.48 Hz, 1 H) , 7.33 (t, J=7.70 Hz, 1 H) , 7.20 (d, J = 7.58 Hz, 1 H) , 6.89 (d, J=1.96 Hz, 1 H) , 6.65 (d, J = 8.56 Hz, 1 H) , 5.65 (q, J = 6.85 Hz, 1 H) , 3.84 (m, 1 H) , 3.25 (m, 1 H) , 2.95 -3.03 (m, 1 H) , 2.75 -2.95 (m, 2 H) , 2.54 -2.75 (m, 1 H) , 2.47 (s, 3 H) , 1.86 (d, J=6.97 Hz, 3 H) .

D. Biological assays and data

The compounds of present invention are Na _v1.7 inhibitors, and are useful in the treatment of disorders mediated by Na _v1.7 activity. The biological activities of the compounds of present invention can be determined using any suitable assay which measures if a compound inhibits Na _v 1.7 activity, as well as tissue and in vivo models.

It is understood that the data described herein may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments.

1) Na _v1.7 channel QPatch assay

This assay was used to measure the ability of a compound to block the Na _v1.7 channel. CHO (Chinese Hamster Ovary) cells obtained from Genionics AG (Zurich, Switzerland) , which stably express human Na _v1.7, were used in the assay. The whole cell QPatch recording was conducted at room temperature on QPatch 16X or QPatch HTX (Sophion Biosciences) . The extracellular solution consisted of 140 mM NaCl, 3 mM KCl, 1 mM CaCl ₂, 1 mM MgCl ₂, 0.1 mM CdCl ₂, 5 mM HEPES, and 20 mM TEA-Cl. The pH of the extracellular solution was 7.3, and the osmolarity was 310-320 milli-osmole (mOsm) . The intracellular solution consisted of 10 mM NaCl, 10 mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES) , 1 mM ethylene glycol tetraacetic acid (EGTA) , 140 mM CsF, and 5 mM CsOH. The pH of the intracellular solution was 7.3 and the osmolarity was 280-290 mOsm. The cell culture medium consisted ofF12 Hams, 10%Fetal bovine serum (FBS) , 0.1 mg/ml G418/Geneticin, and 0.1 mg/ml hygromycin B (all from Invitrogen) . Cultured Na _v1.7 CHO cells were harvested with TrypIE (Invitrogen) and re-suspended in the extracellular solution. Tested compounds in DMSO solution were diluted in DMSO to different stock concentrations and then further diluted in the extracellular solution to achieve the final test concentration, with DMSO content at no more than 0.3%by volume. For QPatch recording, three additions of 5 μl of the vehicle (DMSO solution with no tested compound) were added. Then, the cell was applied the voltage protocol for 30 runs to reach a baseline period. After that, five concentrations (0.001 μM, 0.01 μM, 0.10 μM, 1.00 μM and 10.00 μM) of each test compound in DMSO solution were tested in an ascending manner. Three additions (5 μl x 3) were added for each concentration. The exposure of Na _v1.7 CHO cells in the test compound at each concentration was generally no less than 5 minutes until the current was stabilized in each concentration. Voltage protocol: the voltage was increased to -70 mV from the holding potential of -120 mV for 8 s (prepulse) to inactivate sodium channels. Then the voltage was stepped back to -120 mV holding potential for 20 milli-seconds (ms) , and then the voltage was stepped to -10 mV for 20 ms to open sodium channels. Finally, the voltage was stepped back again to -120 mV holding potential. The voltage command protocol was repeated every 15s continuously during the test. The concentration response curves were fitted into a four parameter Hill equation using the QPatch Assay Software to derive IC ₅₀ values.

Examples 1-101 were tested in the Na _v1.7 channel QPatch assay described above and were found to inhibit Na _v1.7 activity (IC ₅₀ less than 10.0 μM) in at least one experiment. The IC ₅₀ values in the Na _v1.7 channel QPatch assay for Examples 1-4, 15, 18, 25, 27-30, 36, 39, 48, 49, 54, 56, 63-66, 73, 74, 76, 81, 88, 93, 94 and 100 were less than 0.1 μM in at least one experiment.

2) Na _v1.7 channel manual patch clamp assay

This assay was used as an alternative method to measure the ability of a compound to block the Na _v1.7 channel. In house HEK293 cells stably expressing human Na _v1.7 channel were used in the assay. The whole cell manual patch clamp recording was conducted at room temperature on a Multiclamp 700B patch-clamp amplifier (Molecular Devices, U.S.A) . Output signals from the amplifier were digitized using a DigiData 1550 A/D-D/Aboard. The recording was controlled with Pclampl0 software (Molecular Devices, U.S.A) . The extracellular solution consisted of 50 mM NaCl, 85mM Choline-Cl, 5.4 mM KCl, 2 mM CaCl ₂, 1 mM MgCl ₂, 10 mM HEPES, and 5mM glucose. The pH of the extracellular solution was 7.4, and the osmolarity of the extracellular solution was 305 mOsm. The intracellular solution consisted of 85 mM Cs-methanesulfonate, 35 mM CsF, 20 mM CsCl, 5 mM NaCl, 5 mM EGTA 5, 10 mM HEPE. The pH of the intracellular solution was 7.3, and the osmolarity was 295 mOsm. The cell culture medium consisted of DMEM/F12 with 20%FBS, 2 mM GlutaMAX, 0.1 mM NEAA and 400 μg/ml G418B (all from Invitrogen) . The tested compounds in DMSO were diluted by adding DMSO to different stock concentrations and then further diluted in the extracellular solution to achieve the final test concentration, with DMSO content at no more than 0.3%by volume. For patch clamp recording, the cell was continuously perfused with extracellular solution from a perfusion system (SF-77B, Warner Instruments, ～1 ml/min) mounted on the stage of an inverted microscope (Zeiss AXI0, Germany) . The perfusion tip was manually positioned under microscope. In this assay, two voltage protocols are sequentially applied in each cell. The voltage-dependence of inactivation was first determined by applying a series of 1s-long depolarizing prepulses ranging from -120 to -20 mV with 5 mV increments and 5 s sweep intervals from a holding potential of -120 mV. The voltage was then immediately stepped to -10 mV to assess the magnitude of the sodium current. Peak currents elicited at -10 mV were plotted as a function of prepulse potential and the I-V curve was fitted by Clampfit 10.5 software to estimate the midpoint of inactivation V1/2. Then, the inactivated state protocol was applied to estimate the compound effect on Nav1.7 currents. Cell membrane was depolarized to a conditioning prepulse voltage of V1/2 for 8 s from a holding potential of-120 mV and then was hyperpolarized to -120 mV for recovery with 20-ms duration. A test pulse to -10 mV for 20 ms was applied after recovery. The stimulation was applied every 15s. The peak current amplitudes at test pulse of-10 mV were analyzed to generate I-T (current-time) plot. During the recordings, single concentration of compound was applied to the cell for 20 min to obtain a steady-state inhibition effect before 5-min stable baseline in 0.1%DMSO solution. The fitting of the dose-response curves was carried out with Prism 6.0 software using a four-parameter Hill’s equation to derive IC ₅₀ values.

Examples 64-66, 74, 76, 93-95, 99-101 were tested in the Na _v1.7 channel manual patch clamp assay described above and were found to inhibit Na _v1.7 activity (IC ₅₀ less than 1 μM) in at least one experiment.

3) Na _v1.5 channel manual patch clamp assay

This assay was used to measure the ability of a compound to block Na _v. 1.5 channel. HEK293 cells generated by WuXi Apptec (Shanghai, China) , which stably express human Na _v1.5, were used in the assay. The whole cell manual patch clamp recording was conducted at room temperature on a Multiclamp 700B patch-clamp amplifier (Molecular Devices, U.S.A) . Output signals from the amplifier were digitized using a DigiData 1440 A/D-D/Aboard. The recording was controlled with Pclampl0 software (Molecular Devices, U.S.A) . The extracellular solution consisted of 140 mM NaCl, 3 mM KCl, 1 mM CaCl ₂, 1 mM MgCl ₂, 0.1 mM CdCl ₂, 5 mM HEPES, and 20 mM TEA-Cl. The pH of extracellular solution was 7.3 and the osmolarity of the solution was 310-320 mOsm. The intracellular solution consisted of 10 mM NaCl, 10 mM HEPES, 1 mM EGTA, 140 mM CsF, and 5 mM CsOH. The pH of the intracellular solution was 7.3 and the osmolarity was 280-290 mOsm. The cell culture medium consisted of (Dulbecco′s Modified Eagle Medium: Nutrient Mixture F-12 (DMEM/F12) , 10%FBS 0.25 mg/ml G418/Geneticin, 1%non-essential amino acid (NEAA) , and 1%GlutaMax (all from Invitrogen) . The test compounds in DMSO were diluted in DMSO to different stock concentrations and then further diluted in the extracellular solution to reach the final testing concentration, with DMSO content at no more than 0.3%by volume for patch clamp recording, the cell was continuously perfused with extracellular solution from a perfusion system (Biologic Rapid solution changer, RSC-160, ～lml/min) mounted on the stage of an inverted microscope (Nikon Ti-S, Japan) . The perfusion tip was manually positioned under microscope. During the initial recording period, the peak current amplitude was monitored until being stable (＜ 5%change) for 5～10 sweeps. Once the peak current amplitude was stabilized, the solution of the tested compound started with the lowest concentration and continued until the peak current was again stable for 5～10 sweeps, or 5 minutes if peak current did not change. Five concentrations (0.001 μM, 0.01 μM, 0.10 μM, 1.00 μM and 10.00 μM) were tested for each compound and each test was repeated at least twice. The voltage protocol was described below: first, the voltage was stepped to actual V _half for 8 s (prepulse) from the holding potential of-120mV to inactivate sodium channels. Then, the voltage was stepped back to -120mV holding potential for 20 ms, and then the voltage was stepped to -10mV for 20 ms to open sodium channels. Finally, the voltage was stepped back again to -120mV holding potential. This voltage command protocol was repeated every 15 s continuously during the test. The concentration response curves were fitted into a four parameter Hill equation using Clampfit (V10.2, Molecular Devices) to derive IC ₅₀ values.

Examples 54 and 56 were tested in the Na _v1.5 channel manual patch clamp assay described above in one experiment and were found not to inhibit Na _v1.5 activity (IC ₅₀ greater than 10.0 μM) .

4) Human bronchiole assay

Compounds were assessed by their ability to block electrical field stimulation (EFS) -induced human bronchi contractions. Compound potency (expressed as IC ₅₀) and efficacy (expressed as % inhibition) were assessed in a human bronchiole preparation as outlined in Kocmolova et al., J. Pharmacol. Exp. Ther. 361 (1) : 172-180 (2017) .

Human bronchi are innervated by parasympathetic fibers of the vagal nerve, stimulation of this nerve releases acetylcholine resulting in contraction of the bronchi (bronco-constriction) . The vagal nerve endings express Na _v1.7 with bronchoconstriction being dependent on Na _v1.7-dependent neurotransmitter release (see Kocmolova et al. for expression profiling and pharmacological evidences) . Thus, this biological system can be utilized to assess the potency of Na _v1.7-selective compounds in a functional human tissue.

Test compounds were bath applied to human bronchi in a cumulative dose/response method including the following concentrations (0.01, 0.1, 1, 10 μM) . Compound effects were measured as reductions of electrical field stimulation-induced contractions and quantified as %inhibition, IC ₅₀ values were derived from the dose/response curve where compound concentration is plotted as a function of %inhibition.

5) Rapid Equilibrium Dialysis Protein Binding Assay

The Rapid Equilibrium Dialysis (RED) system was used to measure the in vitro unbound fraction of test compounds in plasma, blood or tissue homogenates. Test compounds solutions were prepared in human plasma or in phosphate-buffered saline (PBS) diluted blood (1: 1 v/v) from Wistar Han rat, beagle dog, bama minipig or human at a concentration of 2 micromolar. Potassium ethylenediaminetetraacetic acid (EDTA) was used as the anticoagulant. All human materials were ethically sourced from approved suppliers. Triple-replicates of each test compound solution were placed into individual donor chambers of the RED device inserts; the membranes used were 8000-molecular weight cut-off. The receiver chambers of the RED devices were filled with PBS. The RED devices were incubated with gentle shaking on an orbital shaker for 4 hours at 3℃ to allow the test compounds to equilibrate across the donor and receiver chambers. Samples were collected from the donor and receiver chambers and test compound: internal standard peak area ratios were determined with test compound-specific liquid chromatography tandem mass spectrometric (LC-MS/MS) methodologies. The unbound fraction of test compound was calculated with the following sets of equations:

Fu = (1/D) / { [ (1/Apparent Fu) -1] + (1/D) } (1)

where D is the dilution factor.

Apparent Fu = [ARB/SCFB] / [ARM/SCFM] (2)

where:

ARB = Area ratio of buffer chamber,

ARM = Area ratio of matrix sample chamber,

SCFB = Sample correction factor Buffer,

SCFM = Sample correction factor Matrix.

SCFB = Sample volume buffer/ (sample volume of buffer + sample volume of matrix) (3)

SCFM = Sample volume matrix/ (sample volume of buffer + sample volume of matrix) (4)

6) Fasted State Simulated Intestinal Fluid (FaSSIF) Solubility Assay

Fasted State Simulated Intestinal Fluid (FaSSIF) preparation: solution A1 -lecithin and sodium taurocholate were added to 10%of the final water volume and the solution was stirred. After lecithin was fully dissolved and the solution clarified, the remaining amount of water was added; solution B1 -KH ₂PO ₄ and KCl were first dissolved in 70%of the final water volume, 0.1M NaOH was added and then the remaining amount of water was added. pH of solution B 1 was adjusted with NaOH or HCl with the target pH being 6.4 + 0.1. One volume of solution A1 was mixed one volume of solution B1 with the target pH being 6.5 ± 0.1. The final composition of FaSSIF (pH6.5) was as follows: 0.75 mM lecithin, 3.0 mM sodium taurocholate, 0.030 M KH ₂PO ₄, 0.10 M KCl and 0.01 M NaOH.

Test compounds were prepared at suspensions at nominal concentration of 1 mg/mL in FaSSIF (total volume 1 mL) . The suspensions were incubated 37℃ in a water bath shaker. Samples (400 uL) of the suspensions were collected at 4 hour and 24 hour, and immediately centrifuged at 14,000 revolutions per minute (rpm) for 10 min. Aliquots (200 uL) of the resultant supernatants were collected and diluted with an equal volume of a 50%aqueous acetonitrile solution. The prepared samples were analyzed by ultra performance liquid chromatography (UPLC) . Test compound concentration (FaSSIF solubilty) was determined by comparison of the UPLC signal with a calibration curve for specific to the test compound prepared at known concentrations.

Examples 65 and 99 were tested in the FaSSIF solubility assay described above. In one experiment, solubility of Example 65 was 449 ug/ml at 4 hour and 501 ug/ml at 24 hour, and solubility of Example 99 was 608 ug/ml at 4 hour and 711 ug/ml at 24 hour.

E. Methods of use

The compounds of the invention are inhibitors of Na _v1.7. Therefore, these compounds may be used in therapy in the treatment of disorders mediated by Na _v1.7 activity.

In one embodiment, the present invention provides methods for the treatment of pain which comprise administering to a subject in need thereof with a therapeutically effective amount of a compound of the invention. Exemplary pain disorders include, but are not limited to, neuropathic pain; inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) ; nociceptive pain (e.g., post-surgical pain, cancer pain, back and orofacial pain, osteoarthritis, dental pain, diabetic peripheral neuropathy) , postherpetic neuralgia; musculoskeletal pain; visceral pain, lower back and neck pain; sprains and strains; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; pain associated with maycer and chemotherapy, pain associated with HIV, pain induced by HIV treatment, pain associated neuropathy, pain associated nerve injury, pain associated root avulsions, painful traumatic mononeuropathy, painful polyneuropathy, erythromyelalgia, paroxysmal extreme pain disorder (PEPD) , burning mouth syndrome, central pain syndromes (e.g., potentially caused by virtually any lesion, at any level of the nervous system) , postsurgical pain syndromes (e.g., post mastectomy syndrome, post thoracotomy syndrome, stump pain) , bone and joint pain (osteoarthritis) , repetitive motion pain, dental pain, myofascial pain (e.g., muscular injury, fibromyalgia) , perioperative pain (e.g., general surgery, gynecological) , chronic pain, dysmennorhea, pain associated with angina, inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disorder, teno-synovitis and gout) , shoulder tendonitis or bursitis, gouty arthritis, and aolymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic arthritic pain and related neuralgias acute pain, migraine, migraine headache, headache pain, cluster headache, non-vascular headache, traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP) , dysmenorrheal, primary erythromelagia, HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP) , carpal tunnel syndrome, and vasculitic neuropathy.

In some embodiments, the present invention provides methods of treatment of neuropathic pain. Neuropathic pain includes peripheral neuropathic pain and central neuropathic pain. Neuropathic pain can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain is traditionally classified according to the disorder or event that precipitates them. Exemplary neuropathic pain include: inherited erythromelalgia (IEM) , small fiber neuralgia (SFN) and neuroma pain, diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, chronic lower back pain, phantom limb pain, chronic pelvic pain, vulvodynia, and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias) , increased sensitivity to touch (hyperesthesia) , painful sensation following innocuous stimulation (dynamic, static or thermal allodynia) , increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia) , continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia) .

In one embodiment, the present invention provides methods of treatment of pain selected from the group consisting of inherited erythromelalgia (IEM) , small fiber neuralgia (SFN) , and paroxysmal extreme pain disorder (PEPD) .

In one embodiment, the present invention provides methods of treatment of neuropathic pain selected from the group consisting of neuropathic back pain and painful diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia.

In some embodiment, the present invention provides methods of treatment of inflammatory disorders, for example in the treatment of skin conditions (e.g. sunburn, bums, eczema, dermatitis, psoriasis) ; ophthalmic disorders; lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, non-allergic rhinitis, cough, respiratory distress syndrome, pigeon fancier’s disorder, farmer’s lung, chronic obstructive pulmonary disorder, (COPD) ; gastrointestinal tract disorders (e.g. Crohn’s disease, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease) ; other conditions with an inflammatory component such as migraine, multiple sclerosis, myocardial ischemia.

In some embodiments, the present invention provides methods of treatment of epilepsy including post-traumatic epilepsy, obsessive compulsive disorders (OCD) , sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy) , tics (e.g. Giles de la Tourette′s syndrome) , ataxias, muscular rigidity (spasticity) , and temporomandibular joint dysfunction.

In one embodiment, the present invention also provides uses of compounds of the invention in the manufacture of a medicament for treating disorders described herein.

In one embodiment, the present invention also provides compounds of the invention for use in the treatment of disorders described herein.

In one embodiment, the present invention also provides compounds of the invention for use in therapy.

F. Composition

The compounds of the present invention may be formulated into pharmaceutical compositions prior to administration to a subject. Accordingly, one aspect of the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient. In accordance with another aspect of the invention, a process is provided for the preparation of a pharmaceutical composition including admixing a compound described above or salts thereof, solvates etc thereof, with one or more pharmaceutically acceptable excipient.

Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, from 0.1 to 1000 mg of a compound of the present invention, depending on the condition being treated, the route of administration and the age, weight and condition of the subject, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. In other embodiments, the unit dosage compositions are those containing a daily dose or sub-dose as described herein, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known to one skilled in the art.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication. However, a therapeutically effective amount of a compound of present invention for the treatment of the disorder described herein will generally be in the range of 0.1 to 100 mg/kg body weight of recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for example, for a 70 kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or in a number of sub-doses per day as such as two, three, four, five or six doses per day. Or the dosing can be done intermittently, such as once every other day, once a week or once a month. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.

The pharmaceutical compositions of the invention may contain one or more compounds of the invention. In some embodiments, the pharmaceutical compositions may contain more than one compound of the invention. For example, in some embodiments, the pharmaceutical compositions may contain two or more compounds of the invention. In addition, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical compositions. Each excipient may be compatible with the other ingredients of the pharmaceutical compositions when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.

The compounds of the invention and the pharmaceutically acceptable excipient or excipients may be formulated into a dosage form adapted for administration to the subject by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) nasal inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration (including buccal, sublingual or transdermal) such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Such compositions may be prepared by any methods known in the art of pharmacy, for example by bringing into association a compound described above with the carrier (s) or excipient (s) .

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Suitable pharmaceutically acceptable excipients may vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the compositions. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate carrying or transporting the compound or compounds of the invention once administered to the subject from an organ, or a portion of the body, to another organ, or a portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington′s Pharmaceutical Sciences (Mack Publishing Company) , The Handbook of Pharmaceutical Additives (Gower Publishing Limited) , and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press) .

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington′s Pharmaceutical Sciences (Mack Publishing Company) .

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch) , cellulose and its derivatives (e.g. microcrystalline cellulose) , calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch) , gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose) . The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

In certain embodiment, the present invention is directed to a pharmaceutical composition comprising 0.01 to 1000 mg of one or more compounds described above described herein or a pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention is directed pharmaceutical compositions for the treatment of pain (e.g., neuropathic pain) comprising a compound described herein or a pharmaceutically acceptable salt thereof.

Claims

A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein

- R1 is selected from the group consisting of:

i) cyclopropyl substituted with piperidinyl or C _1-3alkyl;

wherein:

the C _1-3alkyl is substituted with piperidinyl or NH ₂;

ii) phenyl substituted with (CH ₂) _mNRxRy;

wherein:

m is 1 or 2, Rx is H or methyl;

Ry is H, methyl, CH ₂CH ₂OH, CH ₂COOH or CH ₂CH ₂NH ₂;

iii) phenyl substituted with methyl;

wherein:

the methyl is substituted with one to three substituents independently selected from the group consisting of OH, halo, CH ₂NH ₂ and morpholinyl;

iv) phenyl substituted with 4 to 6 membered heterocycloalkyl;

wherein:

the heterocycloalkyl is optionally substituted with one substituent selected from the group consisting of methyl, halo and methoxy;

v) phenyl substituted with two substituents independently selected from the group consisting of halo and C _1-3alkyl;

wherein:

the C _1-3alkyl is optionally substituted with one substituent selected from the group consisting of NH ₂, N (CH ₃) ₂ and NHCH ₂ (C=O) NH ₂;

vi) phenyl substituted with tetrahydropyridinyl;

wherein:

the tetrahydropyridinyl is optionally substituted with methyl;

vii) tetrahydroisoquinolinyl;

wherein:

the tetrahydroisoquinolinyl is optionally substituted with methyl;

viii) tetrahydronaphthalenyl;

wherein:

the tetrahydronaphthalenyl; is optionally substituted with NH ₂ or OH;

- R2 is H or halo and R3 is H or halo;

wherein:

one of R2 and R3 is H and the other is halo;

- R4 is methyl or H; and

- Het is 5 or 6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, S and O; and

wherein:

the heteroaryl is optionally substituted with one substituent selected from halogen, C _1-3alkyl and CN.
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is phenyl substituted with 4 to 6 membered heterocycloalkyl;

wherein:

said heterocycloalkyl is optionally substituted with one substituent selected from the group consisting of methyl, halo and methoxy.
The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R1 is phenyl substituted with piperidinyl;

wherein:

the piperidinyl is optionally substituted with methyl.
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is phenyl substituted with tetrahydropyridinyl;

wherein:

the tetrahydropyridinyl is optionally substituted with methyl.
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is tetrahydroisoquinolinyl;

wherein:

the tetrahydroisoquinolinyl is optionally substituted with methyl.
The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 5, wherein R2 is H and R3 is F.
The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 5, wherein R2 is F and R3 is H.
The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 7, wherein Het is selected from the group consisting of thiazolyl, pyridinyl, isoxazolyl and thiadiazoly;

wherein:

the Het is optionally substituted with halo, C _1-3alkyl or CN.
The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 8, wherein Het is thiazol-4-yl.
The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 8, wherein Het is thiadiazolyl.
The compound according to claim 1 is (R) -7-fluoro-2-oxo-3- (1- (1, 2, 3, 4-tetrahydroisoquinolin-8-yl) ethyl) -N- (thiazol-4-yl) -2, 3-dihydrobenzo [d] oxazole-6-sulfonamide or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 is (R) -7-fluoro-3- (1- (2- (1-methyl-l, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) ethyl) -2-oxo-N- (thiazol-4-yl) -2, 3 -dihydrobenzo [d] oxazole-6-sulfonamide hydrochloride or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising:

a) a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12; and

b) at least one pharmaceutically acceptable excipient.
A method for treating a disorder mediated by Na _v1.7 activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12 or a pharmaceutical composition according to claim 13.
The method according to claim 14, wherein the disorder is pain.
The method according to claim 15, wherein the disorder is neuropathic pain.
A method for treating pain in a subject in need thereof comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12 or a pharmaceutical composition according to claim 13.
A method for treating neuropathic pain in a subject in need thereof comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12 or a pharmaceutical composition according to claim 13.
A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, for use in therapy.
A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12 or a pharmaceutical composition according to claim 13 for use in the treatment of pain.
Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 in the manufacture of a medicament for use in the treatment of pain.